/ 


THE  LIBRARY 

OF 

THE  UNIVERSITY 

OF  CALIFORNIA 

LOS  ANGELES 

GIFT  OF 


Mrs,  Richard  C.  MacCloskey 


MATERIA  MEDICA:  PHARMA- 
COLOGY :  THERAPEUTICS 
PRESCRIPTION  WRITING 
FOR  STUDENTS  AND  PRACTITIONERS 


BY 

WALTER  A.  BASTEDO,  Ph.G.,  M.D. 

Associate  in  Pharmacology  and  Therapeutics  at  Columbia  Univer- 
sity;    Assistant  Attending   Physician   to  St.   Luke's    Hospital, 
New  York    City;      Consulting  Gastro-Enterologist  to  the 
Smith's    Infirmary    and    to    the   Red    Cross  Hospital; 
Consulting    Physician    to  St.   Vincent's  Hospital, 
Staten     Island;     Fifth   Vice-President  of    the 
National  Convention  for  the  Revision  of 
the  United  States  Pharmacopoeia;  for- 
merly Curator  of  the  New  York 
Botanical  Garden 


ILLUSTRATED 


PHILADELPHIA    AND    LONDON 

W.  B.  SAUNDERS  COMPANY 

1913 


Copyright,  1013,  by  W.  B.  Saunders  Company 


AUTHORITY        TO  USE         FOR       COMMENT         THE         PHARMA- 

COPOEIA OF  THE  UNITED  STATES  OF  AMERICA.  EIGHTH 
DECENNIAL.  REVISION.  IN  THIS  VOLUME,  HAS  BEEN 
GRANTED  B  •  THE  BOARD  OF  TRUSTEES  OF  THE 
UNITED  STATE?  PHARMACOPOEIAL  CONVENTION, 

WHICH  BOARD  OF  TRUSTEES  IS  IN  NO  WAY  RESPONSIBLE 
FOR  THE  ACCURACY  OF  ANY  TRANSLATIONS  OF  THE 
OFFICIAL  WEIGHTS  AND  MEASURES,  OR  FOR  ANY  STATE- 
MENTS    AS      TO      STRENGTH      OF      OFFICIAL     PREPARATIONS 


PRINTED    IN    AMERICA 

PRESS    OF 

W.     B.     SAUNDERS     COMPANY 
PHILADELPHIA 


Library 


DEDICATED  TO 

Professor  ^)cnrp  JmrU  Kttsbp, 

BOTANIST,    PHARMACOGNOSY,    AND  DEAN   OF  THE   FACULTY  OF   THE    NEW   YORK 
COLLEGE  OF  PHARMACY  (COLUMBIA  UNIVERSITY) 

Dear  Doctor  Rusby: 

Will  you  do  me  the  honor  to  accept  this  dedication  as  a  token  of  appre- 
ciation of  your  high  ideals  and  of  your  indefatigable  efforts  in  the  cause 
of  pure  drugs,  and  as  an  expression  of  my  great  personal  debt  to  you,  my 
earliest  and  latest  preceptor  in  the  field  of  "materia  medica"? 

Sincerely  yours, 

Walter  A.  Bastedo 


G76754 


PREFACE 


This  book  is  an  adaptation,  for  the  most  part,  of  lectures 
delivered  at  Columbia  University.  In  its  preparation  I  have 
kept  in  mind  that  the  physician's  reason  for  the  study  of  remedies 
is  the  "treatment  of  the  sick";  and  I  have  laid  most  stress  upon 
those  things  that  bear  on  practice,  even  to  the  exclusion  of  some 
matters  of  great  interest  in  pharmacology. 

But  I  have  endeavored  throughout  to  emphasize  the  value 
of  research,  both  in  the  laboratory  and  at  the  bedside,  and  to 
point  out  any  discrepancy  between  the  value  of  a  remedy  as 
established  by  research  and  its  supposed  value  in  therapeutics. 
For  I  recognize  that,  as  the  result  of  research,  many  of  the 
hitherto  highly  valued  drugs  are  falling  into  merited  disuse;  and 
that  some  that  were  of  little  value  because  of  a  wrong  under- 
standing of  their  action  have  come  to  have  a  definite  place  in 
our  therapeutic  armamentarium.  Indeed,  I  have  given  place  to 
many  remedies  which  I  do  not  recommend,  but  mention  only  to 
condemn. 

I  believe  that,  as  the  outcome  of  critical  laboratory  research 
and  the  adoption  of  laboratory  methods  in  clinical  research,  we 
are  at  the  dawn  of  a  new  era  of  simple  and  practical  therapeutics, 
an  era  in  which  knowledge  will  supplant  credulity,  on  the  one 
hand,  and  skepticism,  on  the  other,  and  in  which  fewer  drugs  will 
be  used  but  better  treatment  given. 

Both  because  of  the  importance  of  digitalis  as  a  drug  and 
because  of  the  recent  great  changes  in  our  knowledge  of  cardiac 
physiology  and  therapeutics,  I  have  discussed  digitalis  at  greater 
length  than  other  drugs;  and  have  drawn  my  conception  of  its 
action  as  much  from  recent  clinical  studies  (my  own  and  those 
of  other  investigators)  as  from  those  of  the  pharmacologic  labor- 
atory. In  the  chapter  on  Prescription-writing  I  have  adopted 
one  method  for  the  students  to  learn;  and  to  avoid  confusion 
have  omitted  mention  of  other  methods,  without  any  intention 
to  imply  that  they  are  inferior. 

Recognizing  that  in  a  subject  which  derives  so  much  from 
research  in  all  the  branches  of  medicine  it  would  be  impossible 
for  one  person  to  be  equally  familiar  with  all  parts,  I  have  drawn 
freely  on   the    published    researches    in   chemistry,   pharmacy, 

13 


14  PREFACE 

physiology,  bacteriology,  and  clinical  medicine.  But  I  have  felt 
that  citation  of  authors  is,  in  the  main,  impracticable  in  a  work 
of  this  character;  so  for  the  most  part  have  omitted  credit  unless 
this  was  required  for  authority.  Likewise,  I  have  made  no  attempt 
to  compile  extensive  bibliographies.  However,  I  should  like  espe- 
cially to  mention  the  works  on  pharmacology  by  Cushny,  Soll- 
mann,  Schmiedeberg,  Heinz,  and  Meyer  and  Gottlieb;  those  on 
physiology  by  Howell,  Starling,  Schafer,  and  Leonard  Hill;  the 
sundry  publications  of  von  Noorden,  Mackenzie,  Pawlow,  Herter, 
Lee,  Lusk,  Meltzer,  Hatcher,  Hertz,  and  others;  and  the  Herter 
and  Harvey  Society  lectures. 

For  the  use  of  a  number  of  tracings  I  owe  my  deepest  thanks 
to  my  colleague,  Dr.  Charles  C.  Lieb,  whose  care  about  the  de- 
tails of  an  experiment  and  accuracy  in  recording  results  I  believe 
to  be  unsurpassed. 

W.  A.  Bastedo. 

57  West  58TH  St.,  New  York,  N.  Y. 
October,  igi 3 


CONTENTS 


PART   I 

PAGE 

Introduction 17 

The  Constituents  of  Organic  Drugs 19 

Special  Animal  Derivatives 37 

Pharmaceutic  Preparations 37 

Definition  of  the  Kinds  in  Common  Use 40 

Weights  and  Measures 43 

Active  Principles  and  Assay  Processes 44 

The  Pharmacopoeia 45 

Dosage 47 

Factors  which  Modify  the  Dose 48 

Administration 52 

The  Ways  in  which  Drugs  May  be  Administered   for   Systemic   and 

Remote  Local  Effect 52 

The  Time  of  Administration 55 

Sites  and  Modes  of  Action  of  Drugs 56 

Synergists  and  Antagonists 57 

Scientific    and    Empiric    Therapeutics — Animal    Experimentation  58 

The  Scope  of  Treatment 60 

How  Much  Shall  we  Learn  About  Drugs? 61 

The  Pharmacologic  Action 63 

PART   II 

Individual  Remedies 65 

Protectives 65 

Sweetening  Agents 66 

Nutrients 66 

Counterirritants 67 

Caustics  (Escharotics) 73 

The  Digestive  Ferments 76 

The  Inorganic  Acids 81 

The  Organic  Acids 83 

Fruit  Acids 85- 

Antacids 86 

Antacids  of  Alkaline  Reaction 86 

Antacids  not  of  Alkaline  Reaction 94 

Carminatives 95 

Bitters 100 

Anti-bitters 101 

Charcoal 102 

Emetics 102 

Antemetics 104 

Astringents 105 

Anthelmintics 107 

Cathartics no 

Cathartic  Measures 113 

Cathartics  Acting  by  Selective  Affinity 116 

Irritants 1 16 

Very  Weak  Laxatives 116 

Fixed  Oils,  Soaps,  and  Glycerin 118 

Cathartic  Mercurials 120 

Anthracene  Derivatives i-- 

Drastics 125 

15 


1 6  CONTEXTS 

Cathartics  (Continued)  PAGE 

Saline  Cathartics 128 

Rectal  Treatment 134 

anti-diarrheics i36 

Mineral  Waters 136 

Remedies  Whose  Chief  Action  is  Upon  the  Circulation 138 

The  Physiology  of  the  Circulation 139 

General  Circulator}-  Stimulants 147 

Mechanical  Measures  for  Raising  Arterial  Pressure 210 

Remedies  Which  Lower  Blood- pressure 217 

Cardiac  Depressants 217 

Arterial  Dilators 225 

Measures  for  Decreasing  the  Volume  of  the  Blood 231 

Shock  and  Collapse 233 

Remedies  Whose   Chief  Action    is  Upon    the    Central   Nervous 

System 238 

Central  Nervous  Stimulants 238 

Remedies  Which  Depress  the  Central  Nervous  System — Narcotics .  .  266 

General  Anesthetics 267 

Intoxicants 297 

Hypnotics 335 

Antihysterics  (Antispasmodics) 369 

Drugs  Which  Chiefly  Affect  the  Peripheral  Nervous  System.  . .  .  370 

Peripheral  Depressants 370 

Peripheral  Stimulants 411 

Anidrotics 386 

Diaphoretics 419 

Diuretics 425 

Antipyretics 434 

Analgesic  Antipyretics 435 

Anti-malarial  Antipyretics 444 

Antirheumatic  Antipyretics 451 

Disinfectants  and  Antiseptics 459 

Therapeutic  Classification  of  Disinfectants 481 

General  Disinfectants  and  Deodorizers 481 

Preservatives 481 

Disinfectants  for  Surgical  Supplies 482 

Disinfectants  for  Local  Use  About  Body 482 

Disinfectants  to  be  Given  by  Mouth 483 

Heavy  Metals 483 

Thyroid  Gland \ 519 

Antithyroid  Preparations 522 

Expectorants 522 

Emmenagogues 525 

Carbon  Monoxide .        . .  532 

Oxygen 534 

PART  III 

Prescription  Writing 535 

Liquid  Prescriptions 537 

Administration  of  Liquids 539 

Administration  of  Solids 540 

Latin 54! 

The  Form  of  a  Prescription 545 

Figuring  the  Quantities 547 

Abbreviations 551 

Practice  in  Bulk  Prescriptions 553 

Practice  in  Prescriptions  for  Objects  to  be  Counted 555 

Incompatibility 557 

Index 561 


MATERIA  MEDICA, 

PHARMACOLOGY,  THERAPEUTICS, 

AND  PRESCRIPTION-WRITING 


PART  I 
INTRODUCTION 

"Medicine  sometimes  cures,  it  often  relieves,  it  always  consoles." 

The  physician's  calling  has  arisen  from  the  needs  of  the  sick, 
a  person  who  is  ill  desiring  the  services  of  some  one  who  can 
help  him  to  get  well.  If  the  sick  man  cannot  be  made  well, 
he  wants  as  much  improvement  in  his  health  as  possible,  so  that 
he  may  do  things;  for  example,  attend  to  his  business,  or  at 
least  get  about.  If  his  health  cannot  be  improved,  he  wants  his 
comfort  promoted  and  his  life  prolonged.  Thus  the  objects 
of  the  practice  of  medicine  are:  to  prolong  life,  to  secure  comfort, 
to  improve  health,  or  to  promote  recovery. 

The  physician  accomplishes  these  objects  by  doing  something 
for  his  patients,  i.  e.,  by  treating  them.  Therefore  his  ability 
to  treat  his  patients  successfully  is  what  constitutes  his  direct 
personal  value  for  them,  and  is  the  ultimate  raison  d'etre  of  the 
physician's  calling.  Hence  the  importance  of  a  familiarity  with 
the  available  means  of  treatment,  i.  e.,  with  remedial  or  thera- 
peutic measures. 

Therapeutics  is  the  science  of  the  use  of  remedial  measures. 
When  a  physician  orders  a  patient  to  bed,  he  employs  a  thera- 
peutic measure.  Also  when  he  orders  a  cold  bath,  a  cathartic, 
or  the  application  of  a  mustard  plaster;  or  when  he  applies  a 
splint  to  a  broken  arm,  or  removes  an  inflamed  appendix,  or  sits 
by  the  bed  and  calms  a  nervous  patient. 

Preventive  medicine  goes  a  step  further  than  remedial  medicine, 
in  that  it  designs  to  prevent  the  appearance  or  spread  of  disease. 

The  main  therapeutic  and  preventive  measures  may  be 
grouped  as  follows: 

i.  Hygienic — those  which  have  to  do  with  cleanliness,  dis- 
infection, the  prevention  of  the  spread  of  contagion,  ventilation, 

2  17 


1 8  PHARMACOLOGY  AND  THERAPEUTICS 

the  selection  of  a  patient's  bedroom,  care  of  bedding,  clothing, 
etc. 

2.  Mechanical — the  use  of  bandages,  splints,  ligatures, 
catheterization  to  empty  the  bladder,  massage,  gymnastics,  etc. 

j.  Operative — the  performance  of  surgical  and  obstetric 
operations. 

4.  Physical — the  use  of  physical  agents:  heat,  cold,  light, 
electricity,  #-rays,  radium,  etc. 

5.  Hydrotherapeutic — the  external  use  of  water  and  its  modi- 
fications: ice,  cold  water,  hot  water,  and  steam,  in  the  form  of 
baths,  packs,  douches,  etc. 

6.  Dietetic — the  modifications  of  diet  for  the  sick. 

7.  Suggestive  or  psychotherapeutic — suggestion,  hypnotism, 
mental  buoying,  etc.  The  psychic  influence  of  a  physician  is 
of  great  importance,  and  to  reassure  a  patient  when  she  is  fearing 
the  worst,  to  encourage,  to  stimulate  the  energies  and  the  will, 
are  among  the  functions  of  the  physician  and  are  therapeutic 
measures. 

8.  Pharmaceutic — the  use  of  pharmaceutic  or  drug  remedies. 
Materia  Medica. — Drug  remedies  are  known  collectively  as 

the  "materia  medica,"  or  medical  materials.  The  science  which 
deals  with  the  properties  of  drugs  is  called  materia  medica,  or, 
more  correctly,  pharmacology.  It  is  a  term  that  is  employed  in 
a  broad  sense  to  include  everything  relating  to  drugs. 

In  connection  with  drugs,  there  are  several  great  fields  of 
work,  the  most  important  being: 

1.  Pharmacognosy — the  study  of  the  physical  properties  of 
crude  drugs.  The  pharmacognosist  studies  the  methods  by  which 
drugs  are  collected,  their  appearance  on  the  market,  the  char- 
acters by  which  they  may  be  identified  and  their  quality  esti- 
mated, their  adulterants  in  the  whole  and  in  the  powdered  state, 
etc. 

2.  Pharmacy — the  art  of  preparing  drugs  for  use.  Manu- 
facturing pharmacy  is  the  art  of  manufacturing  drugs  into  forms 
suitable  for  use  in  medicine.  Dispensing  pharmacy  is  the  art  of 
making  up  prescriptions.  The  pharmacist  makes  his  knowledge 
tell  on  the  manufacture  of  preparations  and  their  combination 
into  prescriptions.  He  studies  weights  and  measures,  solubilities, 
incompatibilities,  keeping  qualities,  chemic  reactions,  the  extrac- 
tion of  active  principles,  and  the  making  of  preparations  suitable 
for  use  in  the  practice  of  medicine. 

3.  Pharmaceutic  chemistry— the  study  of  the  chemistry  of 
drugs  and  preparations  of  drugs. 

4.  Pharmacodynamics,  or  pharmacology  (in  its  restricted 
sense) — the  study  of  the  action  of  drugs.     The  pharmacologist 


INTRODUCTION 


!9 


studies  the  action  of  drugs  on  the  tissues  and  structures  of  living 
things. 

The  practising  physician  does  not  require  a  knowledge  of 
pharmacognosy,  and  he  needs  only  such  knowledge  of  pharmacy 
as  may  prove  helpful  to  him  in  prescribing  the  drugs  he  desires 
his  patient  to  have.  But  his  knowledge  of  pharmacology  should 
be  extensive. 

Drugs  are  either:  (i)  Pure  chemicals,  such  as  sodium  bi- 
carbonate or  potassium  iodide;  (2)  mixed  mineral  products, 
such  as  petroleum  oil,  vaseline,  or  ichthyol;  or  (3)  certain  animal 
or  plant  parts  or  products.  Of  animal  nature  or  origin  are  musk, 
cantharides,  adrenaline,  lard,  honey;  and  of  plant  nature  or 
origin  are  herbs,  barks,  roots,  leaves,  fruits,  seeds,  resins,  alka- 
loids, etc. 

"Crude  drugs"  are  the  commercial  forms  of  the  natural  animal 
or  plant  drugs  as  they  are  brought  to  the  market.  Their  em- 
ployment in  medicine  is  due  to  the  fact  that  they  contain  or 
yield  more  or  less  definite  chemic  bodies  of  medicinal  value. 
These  bodies  are  known  as  the  "active  constituents."  In  some 
cases  these  constituents  are  found  in  all  parts  of  a  plant,  so  that 
the  whole  plant  is  marketed  as  the  crude  drug;  but  mostly  they 
occur  in  one  part  only,  such  as  the  leaf  or  root,  or  are  stored  in 
greatest  abundance  in  one  part,  so  that  that  part  is  selected  for 
the  market  and  is  the  crude  drug.  Sometimes,  as  in  the  case  of 
opium,  an  exudate  contains  the  active  constituents  and  is  the 
crude  drug,  no  structural  part  of  the  plant  being  marketed  at  all. 
The  crude  drug  of  digitalis  is  the  dry  leaf,  the  leaf  of  the  digitalis 
plant  being  the  chief  depository  of  the  peculiar  constituents  on 
which  digitalis  depends  for  its  medicinal  activity ;  the  crude  drug 
of  rhubarb  is  the  dried  root;  of  peppermint,  the  leaves  and  flower- 
ing tops;  of  cascara,  the  bark;  of  asafetida,  the  dried  milk  juice; 
of  Spanish  fly,  the  whole  dried  insect. 

THE  CONSTITUENTS  OF  ORGANIC  DRUGS 

These  may  be  classified  into:  1.  The  Active  Constituents. 
2.  The  Inert  Constituents. 

The  latter  are  the  cellulose,  wood,  and  other  structural  parts 
of  the  drug,  and  in  some  instances  starch,  albumen,  fat,  wax, 
coloring-matter,  and  other  substances  which  have  no  distinct 
pharmacologic  action,  though  their  presence  in  a  preparation 
may  have  a  modifying  effect  on  the  absorbability  and  activity 
of  the  active  pharmacologic  constituents. 

The  active  constituents  may  be  active  in  two  different  ways, 
viz.:    pharmacologically  active,  i.  e.,  having  an  action  on  living 


20  PHARMACOLOGY   AND   THERAPEUTICS 

animal  tissues,  and  pharmaceulically  active,  i.  e.,  capable  of  causing 
precipitation  or  otherwise  notable  chemic  changes  in  a  prescrip- 
tion or  preparation.  Both  kinds  are  found  in  cinchona  bark, 
which  contains  not  only  quinine  and  other  alkaloids  upon  which 
its  pharmacologic  activity  depends,  but  also  tannic  acid,  an 
astringent  drug.  In  an  ordinary  dose  of  cinchona  the  tannic 
acid  is  too  little  in  amount  to  have  any  important  astringent 
effect,  and  is,  therefore,  not  pharmacologically  active;  yet  if 
the  cinchona  preparation  is  mixed  with  a  preparation  of  iron, 
the  tannic  acid  becomes  pharmaceutical^  active  and  changes 
the  iron  salt  into  ink.  Again,  the  pharmacologically  active 
principles  of  digitalis  are  not  readily  soluble  in  water,  so  an 
aqueous  preparation,  such  as  the  infusion*  would  not  represent 
the  activity  of  digitalis  were  it  not  for  the  fact  that  digitalis  also 
contains  a  body  which  possesses  the  peculiar  property  of  rendering 
the  active  medicinal  principles  soluble  in  water.  This  body 
(digitonin)  is,  therefore,  pharmaceutical^  active,  and  as  such 
is  important. 

A  constituent  is  called  an  active  principle  when  to  it  may  be 
attributed,  either  wholly  or  in  part,  the  physiologic  action  of  the 
drug. 

The  active  constituents  of  organic  drugs  may  be  either: 

a.  Single  chemic  bodies,  or — 

b.  Mixtures  of  such  a  nature  that  separation  into  their  com- 
ponents is  not  advantageous. 

The  classes  of  active  constituents  are: 

A.  The  Single  Chemicals. 

i.  Plant  acids  and  their  salts. 

2.  Alkaloids. 

3.  Neutral  principles. 

4.  Toxalbumins. 

5.  Ferments. 

6.  Sugars,  starches,  and  gums. 

7.  Tannins. 

B.  The  Mixtures. 

1.  Fixed  oils,  fats,  and  waxes. 

2.  Volatile  oils. 

3.  Resins. 

4.  Oleoresins. 

5.  Gum-resins. 

6.  Balsams. 

The  last  three  are  natural  exudations  from  plants. 

1.  Plant  Acids  and  Their  Salts. — The  citric  acid  of  lemons, 
the  tartaric  acid  of  grapes,  benzoic,  cinnamic,  salicylic,  tannic 
acid,  and  some  of  their  salts  are  of  interest  pharmacologically. 


THE   CONSTITUENTS   OF    ORGANIC   DRUGS  21 

Glycyrrhizin,  the  sweet  principle  of  glycyrrhiza  (licorice),  is 
really  glycyrrhizic  acid,  and  is  sweet  to  the  taste  only  in  the  form 
of  alkaline  salts.  It  is  precipitated  and  rendered  tasteless  by 
acids. 

2.  Alkaloids. — These  are  a  class  of  organic  bodies  of  alkaline 
reaction,  composed  of  carbon,  hydrogen,  and  nitrogen,  and  some- 
times other  elements.  The  class  includes  a  great  many  of  our 
most  powerful  drugs.  Their  basic  or  alkaline  nature  gives  the 
name  alkaloid  {alkali  and  eidos,  resembling).  They  possess  the 
power  of  neutralizing  acids  with  the  formation  of  salts,  and  in 
doing  so  take  up  the  acid  without  the  liberation  of  hydrogen. 
In  this  respect  they  resemble  ammonia,  and  differ  from  the  alkali 
metals. 

Na  +  HC1  =  NaCl  +  H. 
NH3  +  HC1  =  NH3.HC1 
C2iH22N202  (strychnine)  +  HC1  =  C2iH22N202.HCl 

Some  of  the  alkaloids  are  strongly  basic,  while  others,  such 
as  caffeine,  are  so  feebly  basic  that  they  are  with  difficulty  made 
to  form  salts  at  all.  Most  -are  monacid,  uniting  one  molecule 
of  the  alkaloid  for  each  basic  hydrogen  in  the  acid.  A  few  are 
diacid.  Quinine  forms  two  different  salts  with  sulphuric  acid, 
viz.,  quinine  sulphate,  the  neutral  sulphate,  in  which  two  mole- 
cules of  quinine  unite  with  one  molecule  of  the  dibasic  sulphuric 
acid,  (C2oH24N202)2.H2S04+7H20,  and  quinine  bisulphate,  the 
acid  sulphate,  in  which  only  one  molecule  of  quinine  unites  with 
each  molecule  of  sulphuric  acid,  C20H24N2O2.H2SO4+7H2O. 
The  uncombined  alkaloids,  to  distinguish  them  from  the  "  alka- 
loidal  salts,"  are  known  as  "pure  alkaloids,"  and  are  not  much 
employed. 

Nomenclature. — To  distinguish  these  basic  substances  from 
the  neutral  principles,  the  United  States  Pharmacopoeia  makes  all 
the  names  of  alkaloids  end  in  ine  (Latin,  ina),  as  quinine  (quinina), 
cocaine  (cocaina);  and  the  names  of  the  neutral  principles  end 
in  in  (Latin,  inum),  as  digitalin  (digitalinum) ,  salicin  (salicinum). 
This  is  a  simple  device  for  distinction,  and  it  serves  a  good  pur- 
pose. It  is  to  be  regretted  that,  owing  presumably  to  foreign 
influence,  this  distinctive  spelling  is  not  followed  in  all  the  text- 
books. The  old  form,  ending  in  ia,  as  quinia,  morphia,  strychnia, 
is  now  obsolete. 

Solubility. — The  pure  alkaloids  are,  as  a  rule,  not  readily 
soluble  in  water,  but  they  dissolve  more  or  less  readily  in  alcohol, 
ether,  chloroform,  and  the  fixed  and  volatile  oils.  The  alkaloidal 
salts,  on  the  contrary,  are  mostly  quite  soluble  in  water,  and 
fairly  so  in  alcohol,  but  dissolve  with  difficulty  in  ether,  chloro- 
form, and  the  oils.     For  example,  atropine,  the  pure  alkaloid, 


2  2  PHARMACOLOGY   AND   THERAPEUTICS 

is  soluble  in  450  parts  of  water,  in  1.5  parts  of  alcohol  or  chloro- 
form, and  in  16.5  parts  of  ether;  while  atropine  sulphate,  the  salt 
in  common  use,  is  soluble  in  0.38  part  of  water,  (less  than  its  own 
weight),  in  3.7  parts  of  alcohol,  in  620  parts  of  chloroform,  and 
in  2140  parts  of  ether.  Commonly  in  practice  we  employ  the 
salts  only,  but  when' a  solution  is  to  be  made  in  oil,  or  chloroform, 
or  ether,  we  must  use  the  pure  alkaloid. 

Incompatibles. — Alkaloids  have  extensive  chemic  affinities, 
and  there  are  many  reagents  which  are  used  in  the  laboratory  as 
tests  or  precipitants  for  them.  As  physicians,  however,  we  need 
know  only  their  common  prescription  incompatibles,  i.  e.,  those 
substances  which  form  precipitates  with  alkaloidal  salts,  and 
which  we  would  be  likely  thoughtlessly  to  add  to  a  prescription 
containing  an  alkaloidal  salt.  Such  common  prescription  in- 
compatibles are: 

1.  Alkalies,  which  combine  with  the  acid  radicle  and  throw 
the  less  soluble  pure  alkaloid  out  of  solution  (some  of  the  alka- 
loids are  destroyed  by  strong  alkalies). 

2.  Tannic  acid,  which  forms  the  comparatively  insoluble 
tannate. 

3.  Iodine,  iodides,  and  bromides,  which  form  the  compara- 
tively insoluble  iodides  and  bromides,  or  double  salts. 

4.  Mercuric  chloride,  which  forms  insoluble  double  salts. 
In  these  cases  it  must  be  borne  in  mind  that  the  alkaloid  is 

merely  rendered  less  soluble  in  water,  so  if  a  large  volume  of 
water  or  a  fair  percentage  of  alcohol  is  present,  the  precipitation 
may  not  occur. 

Physical  Character. — Most  of  the  alkaloids  are  solids,  as 
morphine,  quinine,  and  strychnine.  A  few  of  them  are  volatile 
liquids,  as  nicotine,  pilocarpine,  coniine,  and  lobeline,  but  these 
latter  mostly  form  non-volatile  solid  salts,  which  can  be  readily 
handled.  Some  are  crystalline,  some  amorphous.  Some  are 
deliquescent  and  liquefy  in  moist  air,  as  pilocarpine  chloride; 
others  are  efflorescent  and  lose  weight  in  dry  air,  as  the  sulphate 
of  strychnine  and  the  sulphate  of  quinine.  Some  are  decomposed 
by  the  heat  of  boiling  water;  others  can  stand  much  higher 
temperatures.  Cocaine  is  decomposed  at  about  980  C.  (just 
below  the  boiling-point  of  water),  and  its  solutions  cannot, 
therefore,  safely  be  sterilized  by  boiling.  Some  which  will 
stand  a  higher  temperature  for  a  short  time  are:  aconitine, 
atropine,  brucine,  cevadine,  codeine,  morphine,  narcotine,  and 
strychnine ;  so  that  aqueous  or  alcoholic  liquids  containing  these 
alkaloids  may  be  brought  to  the  boiling-point  without  fear  of 
harm. 

Taste. — The  taste  of  alkaloids  is  bitter — that  of  strychnine 


THE   CONSTITUENTS    OE   ORGANIC   DRUGS  23 

and  quinine  intensely  so;  that  of  morphine,  codeine,  and  caffeine, 
mildly  so. 

Occurrence. — Alkaloids  occur  almost  wholly  in  the  higher 
plants — the  dicotyledons.  A  few  are  found  in  the  lower  plants, 
and  one  of  these,  muscarine,  is  the  poisonous  principle  in  a  few 
of  the  poisonous  mushrooms.  Some  plants  furnish  many  alka- 
loids, opium,  for  example,  yielding  about  nineteen,  and  cinchona 
about  thirty-two.  In  some  cases  one  alkaloid  is  found  in  one  part 
of  the  plant  and  another  in  a  wholly  different  part  of  the  same 
plant;  often  several  are  found  together.  Where  a  number  of 
alkaloids  occur  in  one  plant  they  are  usually  closely  related,  both 
chemically  and  pharmacologically,  as  in  the  case  of  the  alkaloids 
of  belladonna;  but  in  some  instances  they  are  quite  different, 
and  may  even  be  pharmacologically  antagonistic,  as  physostig- 
mine  and  calabarine  in  the  Calabar  bean. 

It  is  of  interest  that  some  alkaloids  are  confined  entirely  to 
one  botanical  family,  as  atropine,  which  is  not  found  outside  of 
the  potato  family  {Solanacece);  or  to  one  plant  genus,  as  pilo- 
carpine; or  to  a  particular  species,  as  morphine  in  the  oriental 
poppy,  and  even  then,  perhaps,  only  when  it  is  grown  in  a  par- 
ticular region.  Others,  however,  are  of  wider  distribution,  as 
caffeine,  which  is  found  in  various  parts  of  the  world  in  wholly 
unrelated  plants,  and  berberine,  found  in  the  northeastern  region 
of  the  United  States  in  the  barberry,  hydrastis,  and  moonseed. 

The  amount  of  alkaloid  present  in  different  specimens  of  a 
drug  may  vary  within  wide  limits,  as  might  be  expected  in  plants 
growing  under  such  different  conditions  of  soil,  climate,  and 
weather,  and  subjected  to  different  methods  of  collecting,  drying, 
preserving,  etc.  Yet  the  best  quality  of  most  drugs  is  notably 
uniform  in  its  alkaloidal  content. 

Alkaloids  produced  by  animals  are  more  commonly  known 
as  leukomains  and  ptomains — leukomains,  when  they  are  formed 
by  the  body-cells,  that  is,  are  products  of  metabolism,  for  ex- 
ample, adrenaline;  and  ptomains,  when  they  result  from  micro- 
bic  decomposition  of  dead  material,  especially  the  amino-acids. 
Ptomain-poisoning  from  decomposing  foods  may  closely  resemble 
poisoning  by  plant  alkaloids;  in  fact,  one  ptomain  is  called 
ptomatropine,  because  it  gives  the  symptoms  of  atropine  poison- 
ing. Certain  of  the  alkaloids,  as  choline,  neurine,  xanthine, 
and  some  of  the  ptomains  are  produced  by  both  plants  and  ani- 
mals, so  that  the  dividing-line  is  artificial  and  not  based  on 
chemic  nature. 

Artificial  Alkaloids. — A  number  of  alkaloids  can  be  prepared 
artificially,  and  theophylline,  which  occurs  naturally  in  minute 
quantity  in  tea-leaves,  was  the  first  to  be  produced  synthetically 


24  PHARMACOLOGY   AND    THERAPEUTICS 

on  a  commercial  scale.  Suprarenine,  a  synthetic  with  the  actions 
of  adrenaline,  is  also  marketed.  In  addition,  the  Pharmacopoeia 
recognizes  three  bodies  which  are  manufactured  from  plant 
alkaloids,  viz.,  apomorphine,  prepared  from  morphine  by  dehydra- 
tion; homatr opine,  which  results  from  the  action  of  mandelic 
acid  upon  tropine,  the  mother-substance  of  atropine;  and  hy- 
drastinine,  obtained  by  the  oxidation  of  hydrastine.  Two  other 
artificial  substances  of  the  Pharmacopoeia,  hexamethylenamine,  or 
urotropine,  and  antipyrine,  have  close  chemic  affiliations  with  the 
alkaloid  group. 

That  there  may  be  differences  in  the  physiologic  actions  of 
the  different  salts  of  an  alkaloid  is  suggested  by  the  experiments 
of  0.  H.  Brown,  1907,  on  paramcecium.  For  example,  in  ~ 
solutions  of  quinine  salts  the  paramcecia  lived  in  the  sulphate 
thirty  seconds,  in  the  chloride,  thirty  seconds,  in  the  hypo- 
phosphite,  fifteen  seconds,  in  the  bisulphate,  three  hundred  and 
thirty  seconds.  In  ^  solution  of  strychnine  salts  they  lived 
in  the  acetate  five  seconds,  in  the  nitrate,  forty-five  seconds,  in 
the  sulphate,  seventy  seconds,  in  the  hypophosphite,  seven 
hundred  and  twenty  seconds.  They  were  less  readily  poisoned 
by  ^-  solutions  of  morphine  salts,  so  the  percentage  of  para- 
mcecia dead  at  the  end  of  a  given  time  was  taken.  At  the  end 
of  two  hours,  of  those  in  the  acetate  none  were  dead,  while  of 
those  in  the  valerianate  5  per  cent.,  of  those  in  the  sulphate  60 
per  cent.,  and  of  those  in  the  meconate,  90  per  cent.,  were  dead. 

3.  Neutral  Principles. — Besides  acid  and  basic  substances, 
plants  furnish  a  large  number  of  proximate  principles  which  are 
chemically  neutral.  Their  names  end  in  in  (Latin,  inum),  in 
accordance  with  the  pharmacopceial  rule  to  distinguish  them 
from  alkaloids,  as  stated  above.  The  most  important  are  the 
glucosides  (glycosides) . 

The  glucosides  are  a  class  of  bodies  which,  under  the  in- 
fluence of  certain  agents,  decompose  and  yield  some  form  of 
sugar,  together  with  one  or  more  other  bodies.  These  decom- 
posing agents  may  be  heat,  dilute  acids,  strong  alkalies,  enzymes, 
bacteria,  or  fungi.  Most  of  the  glucosides  yield  glucose,  whence 
the  name;  a  few  of  them  yield  other  sugars.  Chemically,  they 
are  a  loose  group,  and  beyond  their-  readiness  of  decomposition 
and  their  power  to  yield  sugar,  have  no  essential  characters  in 
common.  They  follow  no  rules  as  to  solubility,  or  taste,  or  im- 
portance, some  of  them  being  bitter,  some  not;  some  soluble  in 
water  or  alcohol,  some  not;  some  inert  pharmacologically,  and 
others,  such  as  the  active  principles  of  digitalis,  strophanthus, 
and  cascara,  being  among    our   most   valued    remedies.     The 


THE   CONSTITUENTS    OF    ORGANIC   DRUGS  25 

only  glucosides  official  in  the  United  States  Pharmacopoeia 
are  salicin,  the  active  principle  of  willow  and  poplar  barks,  and 
strophanthine  the  active  principle  of  strophanthus.  The  glu- 
cosidal  nature  of  these  bodies  may  be  readily  shown,  for  if  they 
are  warmed  with  dilute  hydrochloric  acid,  the  mixture  will  give 
the  glucose  test  with  Fehling's  solution.  The  products  of  the 
decomposition  of  salicin  are  glucose  and  saligenin  (salicyl  alco- 
hol). 

C6HnOo.O.C6H4CH2OH  +  H20  =  CeH1206  +  CeH^.OH.CILOH 
Salicin  Glucose  Salicyl  alcohol 

The  ready  decomposition  of  these  bodies  indicates  that  pre- 
parations of  drugs  such  as  digitalis,  which  depend  upon  glucosides 
for  their  activity,  must  neither  be  mixed  with  strong  alkalies  or 
acids  nor  subjected  to  continued  heat. 

There  are  two  glucosides,  amygdalin  and  sinigrin,  which  are 
practically  inert  pharmacologically,  but  are  of  great  importance 
because  of  the  products  of  their  decomposition  by  certain 
enzymes. 

Amygdalin,  with  its  particular  enzyme,  emulsin,  occurs  in 
bitter  almonds,  peach-pits,  wild-cherry  bark,  and  cherry-laurel 
leaves.  In  the  presence  of  water  the  enzyme  emulsin  acts  upon 
the  amygdalin,  causing  it  to  split  up  into  glucose,  hydrocyanic 
acid  (prussic  acid),  and  benzaldehyde.  The  mixture  of  the  two 
latter  constitutes  the  highly  poisonous  volatile  "oil  of  bitter 
almond,"  which  is  required  by  the  Pharmacopoeia  to  contain  not 
less  than  85  per  cent,  of  benzaldehyde  and  2  per  cent,  of  hydro- 
cyanic acid. 

Amygdalin  Water       Glucose        Prussic  acid       Benzaldehyde 

C20H27NOn.3H.2O  +  2H2O  =  2C6H1206  +       HCN        +      C6H5COH      +  3H2O 

The  amygdalin  occurs  in  bitter  almond  to  the  extent  of  1.75 
to  3  per  cent.,  so  that  one  ounce  of  bitter  almonds  would  be  a 
poisonous  dose.  As  enzymes  are  destroyed  by  heat  and  rendered 
inert  by  alcohol,  no  preparation  of  bitter  almond,  wild-cherry 
bark,  or  cherry-laurel  leaves  should  be  made  until  the  drug  has 
first  been  steeped  in  lukewarm  or  cold  water  to  permit  this  enzyme 
action  and  the  development  of  these  products.  If  the  crude  drug 
should  be  extracted  in  the  usual  way  by  alcohol  or  very  hot  water, 
without  preliminary  steeping,  the  preparation  would  be  inert. 
Sweet  almonds  also  contain  emulsin,  but  no  amygdalin,  hence 
are  inert  pharmacologically  and  may  be  swallowed  ad  libitum. 

Sinigrin,  with  its  peculiar  enzyme,  myrosin,  occurs  in  black 
mustard  seed,  and  to  some  extent  in  horseradish  root.  Mustard 
flour,  as  purchased,  contains  nothing  irritating,  and  has  the  odor 
of  ordinary  flour;  but  as  soon  as  it  is  mixed  with  water,  it  develops 


26  PHARMACOLOGY   AND   THERAPEUTICS 

the  odor  and  irritant  properties  characteristic  of  mustard.  This 
is  because,  in  the  presence  of  water,  the  myrosin  acts  upon  the 
sinigrin  and  splits  it  up  to  yield  glucose,  potassium  bisulphate, 
and  allyl  sulphocyanide,  the  last-named  substance  being  the 
highly  irritating  "volatile  oil  of  mustard." 

Sinigrin  Glucose  Potassium  bisulphate      Allyl  sulphocyanide 

C10H18NS2OioK  =  C6H1206     +  KHSO4  +  C3H6CNS 

As  this  enzyme  is  rendered  inert  by  a  temperature  above 
6o°  C.  (1400  F.),  very  hot  water  should  not  be  used  in  preparing 
a  mustard  poultice  or  a  mustard  foot-bath.  It  is  of  interest  that 
this  volatile  oil  of  mustard,  when  shaken  with  alcohol  and  am- 
monia water,  deposits  more  than  its  own  weight  of  crystals  of 
thiosinamine,  a  drug  which  has  been  used  by  injection  for  the 
removal  of  excessive  scar  tissue.     (See  Part  II.) 

C3H6CNS  +  NHa  =  C3H5CSN2H3. 

White  mustard  seed  also  contains  myrosin,  but  instead  of 
sinigrin,  it  contains  another  glucoside,  sinalbin.  Under  the 
influence  of  myrosin  in  the  presence  of  water  sinalbin  splits  up 
into  entirely  different  products,  viz.,  glucose,  sinapine  sulphate 
(an  alkaloidal  salt),  and  acrinyl  sulphocyanide  (an  irritant  but 
non- volatile  oil). 

Phlorhizin  (phloridzin  or  phlorizin)  is  a  glucoside  obtained 
from  the  bark  of  apple,  pear,  cherry,  and  plum  trees,  especially 
the  bark  of  the  root.  It  is  nearly  insoluble  in  cold  water,  but 
readily  soluble  in  alcohol  and  alkaline  liquids.  Its  administra- 
tion is  followed  by  glycosuria  without  hyperglycemia,  the  gly- 
cosuria resulting  from  changes  in  the  kidneys  by  which  they  are 
made  unable  to  keep  back  the  normal  sugar  in  the  blood;  in 
fact,  there  is  a  hypoglycemia.  In  other  words,  the  "  secretion 
threshold"  of  the  kidneys  for  sugar  (Magnus)  is  lowered.  It  is 
diuretic,  this  action,  according  to  Loewi  (1903),  being  due  to 
the  prevention  of  kidney  reabsorption  by  the  sugar  of  the  urine. 
It  has  been  used  as  a  test  of  the  functional  power  of  the  kidneys. 

Besides  the  glucosides,  there  are  other  neutral  principles 
of  importance  in  medicine,  such  as  santonin,  aloin,  elaterin, 
chrysarobin,  etc.  Some  of  those  whose  chief  characteristic  is 
bitterness,  as  quassin  of  quassia,  and  chamomillin  of  chamomile, 
are  often  spoken  of  as  bitter  principles  or  amaroids. 

4.  Toxalbumins  or  Toxins. — An  extensive  class  of  poisonous 
protein  compounds,  of  which  some  occur  in  plants,  some  consti- 
tute the  poisonous  products  of  bacteria,  and  some  are  the  poison- 
ous agents  in  the  venom  of  snakes,  scorpions,  the  tarantula,  the 
Gila  monster,  and  other  poisonous  animals. 


THE   CONSTITUENTS    OF   ORGANIC   DRUGS 


27 


It  is  characteristic  of  these  substances  that  their  poisonous 
symptoms  come  on  only  after  a  latent  period,  and  that,  in  suscep- 
tible animals,  immunity  to  the  poison  may  be  established  by  the 
repeated  administration  of  small  doses.  This  immunity  is  spe- 
cific, the  immunity  to  one  toxin  conferring  no  protection  from 
poisoning  by  another. 

Aside  from  those  produced  by  bacteria  and  animals,  the  most 
important  known  toxalbumins  are: 

1.  Ricin,  which  occurs  in  the  castor-oil  bean,  the  seed  of 
Ricinus  communis.  The  poisonous  ricin  is  left  behind  in  the 
extraction  of  the  castor  oil;  but  there  have  been  some  cases  of 
poisoning  from  the  ingestion  of  the  whole  seeds.  The  author 
has  met  with  a  case  in  New  York.  The  symptoms  are  violent 
gastro-enteritis  and  collapse. 

2.  Abrin,  which  occurs  in  jequirity  beans  (Abrus  precatorius) , 
the  little  shiny  red  seeds  with  circular  black  spot  which  one  often 
sees  in  the  shops  in  baskets  of  sea-shells.  It  is  used  as  an  irritant 
in  the  eye  in  some  cases  of  corneal  opacity. 

3.  Amanita  toxin,  which  occurs  in  the  death's  head  fungus, 
Amanita  phalloides,  and  is  responsible  for  many  cases  of  mush- 
room poisoning.     (See  under  Muscarine.) 

Hypersusceptibility  to  a  toxalbumin  in  the  pollen  of  certain 
plants  would  seem  to  be  the  explanation  of  the  attacks  of  hay- 
fever  and  hay-asthma  to  which  so  many  people  are  subject 
(Meltzer  and  Auer). 

5.  The  Ferments  or  Enzymes. — The  enzymes  are  a  class  of 
bodies  capable  of  instituting  chemic  changes  without  apparently 
entering  into  the  reaction  or  forming  a  part  of  the  end-products. 
Their  activity  is  very  persistent,  but  not  unlimited.  They  are 
unstable  bodies,  and  are  nearly  all  destroyed  at  a  temperature 
of  about  6o°  C.  (1400  F.).  Examples  are:  invertase,  which  trans- 
forms cane-sugar  into  fructose  and  glucose;  lactase,  which 
changes  sugar-of-milk  into  glucose  and  galactose;  maltose,  which 
converts  maltose  into  glucose;  emulsin  and  myrosin,  of  whose 
reactions  with  certain  glucosides  we  have  spoken,  and  pepsin, 
trypsin,  and  the  other  enzymes  of  the  digestive  tract.  A  number 
of  enzymes  have  a  reversible  action,  i.  e.,  can,  under  certain 
circumstances,  bring  about  changes  just  the  reverse  of  the  usual. 

It  is  not  improbable  that  a  great  many  of  the  metabolic 
changes  going  on  in  the  animal  body  are  brought  about  by  en- 
zymes. The  oxidases,  for  example,  are  concerned  in  the  oxidation 
processes  of  the  tissues. 

6.  The  Sugars,  Starches,  and  Gums. — These  are  carbo- 
hydrates of  very  slight  pharmacologic  action  and  of  little  im- 
portance as  remedies,  but  of  importance  in  dietetics  and  the  arts. 


28  PHARMACOLOGY   AND   THERAPEUTICS 

Cane-sugar  or  common  sugar  (Latin,  saccharum),  C12H22O11, 
is  employed  to  make  the  various  syrups  and  as  a  sweetening  agent. 
It  is  found  in  abundance  in  the  sap  of  the  sugar  maple,  in  sugar- 
cane, in  sorghum,  and  in  the  root  of  the  sugar-beet.  It  dissolves 
in  half  its  weight  of  water  and  is  insoluble  in  alcohol.  It  fer- 
ments with  yeast,  but  does  not  reduce  Fehling's  solution.  Solu- 
tions administered  by  hypodermoclysis  are  rapidly  absorbed  and 
are  nutritive  (Magnus). 

Sugar  of  milk  (Latin,  saccharum  lactis),  C12H22O11,  is  obtained 
from  milk,  and  requires  for  solution  five  times  its  weight  of  water. 
It  reduces  Fehling's  solution,  but  does  not  ferment  with  yeast. 
It  is  not  very  sweet,  and  is  chiefly  used  as  a  nutritive  in  infant- 
feeding  and  typhoid  fever.  In  pharmacy  it  is  employed  as  a 
diluent.  Cheap  brands  of  sugar-of-milk  may  contain  lactic 
acid  and  traces  of  milk  proteins,  which  form  a  nidus  for  bacterial 
growth,  or  they  may  be  adulterated  with  cane-sugar  or  glucose. 

Manna,  derived  from  a  tree  of  the  ash  family  {Fraxinus 
ornus),  contains  the* sugar,  mannite,  C6Hi406,  and  is  laxative. 

Glucose  (dextrose),  C6Hi206,  not  official,  is  a  substance  com- 
mercially and  physiologically  of  great  importance,  but  of  little 
use  in  therapeutics.  For  its  nutritive  properties  it  may  be  added 
to  nutritive  enemata  or  to  saline  fluids  intended  for  injection 
into  the  circulation.  Lazarus-Barlow  recommends  a  solution  of 
2.25  per  cent,  for  intravenous  use  in  shock.  Its  ingestion  as 
food  has  proved  protective  against  the  fatty  degenerations  that 
result  from  ether,  chloroform,  and  alcohol. 

Levulose,  C6H12O6,  a  form  of  sugar  abundant  in  honey  and 
some  fruits,  is  a  carbohydrate  which  has  been  found  in  many 
instances  to  be  more  easily  appropriated  by  diabetics  than  are 
cane-sugar,  glucose,  and  many  starchy  foods  (von  Noorden). 
It  has  been  used  by  Strauss  as  a  test  of  the  functional  power  of 
the  liver,  the  assertion  being  made  that  if  the  levulose  is  re- 
coverable from  the  urine  unchanged,  the  liver  is  seriously  im- 
paired. In  Foster's  experiments  3  out  of  10  normal  cases  re- 
sponded with  levulosuria,  and  only  14  out  of  20  cases  of  well- 
marked  cirrhosis.  Churchman,  Frey,  and  others  obtained  similar 
results.     The  test  cannot,  therefore,  be  depended  upon. 

Corn-starch  (amylum),  C6Hi0O5,  is  the  starch  in  common  use. 
It  is  employed  as  a  dusting-powder  for  the  skin,  or  for  pills  to 
prevent  their  sticking  together,  or  in  the  form  of  starch  water 
as  a  soothing  injection  in  irritative  conditions  of  the  lower  bowel. 
To  make  starch  water,  the  starch  should  first  be  hydrolyzed  by 
mixing  about  a  teaspoonful  with  two  ounces  of  water,  boiling 
until  it  forms  a  translucent  paste,  then  diluting  with  water  to 
one  pint.     It  may  be  made  by  simply  boiling  a  teaspoonful  of 


THE    CONSTITUENTS    OF   ORGANIC   DRUGS 


29 


starch  with  the  requisite  quantity  of  water  at  the  outset,  but 
by  this  method  the  starch  does  not  so  readily  hydrolyze.  Corn- 
starch and  arrowroot  starch  (maranta)  are  used  as  foods.  The 
latter  has  long  had  the  reputation  of  being  the  best  kind  of  starch 
for  the  feeding  of  children  and  invalids,  but  it  is  not  now  so  much 
employed  as  formerly. 

The  gums  are  chemically  closely  related  to  the  sugars  and 
starches.  There  are  two  official,  viz.,  acacia,  which  consists 
chiefly  of  arabinose,  C^H^OnCa,  and  tragacanth,  which  can  be 
made  to  yield  arabinose. 

Acacia  (gum  arabic)  is  soluble  in  water  and  is  demulcent. 
Its  chief  uses  are  pharmaceutic,  as  in  the  manufacture  of  muci- 
lage and  emulsions,  and  to  give  increased  viscosity  to  mixtures 
containing  heavy  insoluble  powders  (so  that  the  powder  may  be 
held  in  temporary  suspension  in  the  liquid  during  the  pouring 
of  the  dose).  Its  solutions  ferment  readily,  turn  sour,  and  be- 
come ropy;  and  it  is  precipitated  from  aqueous  solution  by 
alcohol. 

Tragacanth  does  not  dissolve  in  water,  but  swells  up  and  makes 
an  adhesive  paste. 

Dextrin  (C6Hio05),  known  as  British  gum,  is  prepared  from 
starch,  being  an  intermediate  stage  in  the  change  of  starch  to 
maltose  or  glucose.  It  is  soluble  in  water,  is  sweetish  to  the  taste 
and  slightly  laxative,  and  is  the  chief  ingredient  of  some  of  the 
proprietary  infant-foods.  It  is  the  gum  generally  used  on 
postage-stamps,  and  in  paste  form  is  frequently  employed  for 
attaching  labels. 

Cherry-gum  is  an  insoluble  type  of  gum  of  no  medical  interest. 

A  mucilage  is  an  adhesive,  aqueous  liquid  or  paste  made  from 
a  gum.  The  official  mucilages  are  those  of  acacia,  tragacanth 
(both  used  for  mechanical  purposes),  sassafras  pith  (used  as  a 
soothing  eye-lotion),  and  slippery  elm  (used  in  sore  throat). 

7.  The  Tannins  or  Tannic  Acids. — These  are  a  class  of  im- 
perfectly defined  astringent  bodies  of  the  aromatic  group.  They 
are  all  acids  which  form  salts,  and  some  of  them  are  glucosidal 
in  nature.  They  precipitate  alkaloids,  mercuric  chloride,  and 
other  salts  of  the  heavy  metals,  and  also  proteins  and  gelatin. 
With  iron  compounds  they  make  ink  (blue  to  black  in  some  cases, 
green  in  others),  and  with  the  connective  tissue,  protein,  and 
gelatinous  material  of  hides  they  make  leather.  This  suggests 
the  unwisdom  of  administering  a  gelatin-coated  pill  or  capsule 
at  the  same  time  as  a  tannin-containing  drug.  They  are  freely 
but  slowly  soluble  in  water,  and  readily  soluble  in  alcohol  and 
glycerin.  They  occur  mostly  in  the  bark  of  trees,  and  in  the 
plant-galls  which  result  from  punctures  of  insects.     The  various 


3<D  PHARMACOLOGY   AND   THERAPEUTICS 

tannins  are  given  the  names  of  the  plants  which  yield  them, 
e.  g.,  that  from  cinchona  is  called  cinchotannin,  or  cinchotannic 
acid,  that  from  kino  is  kinotannic  acid,  etc.  The  official  "tan- 
nic acid"  is  quercitannin,  and  is  derived  from  oak-galls.  It  is 
considered  in  Part  II. 

8.  The  Fixed  Oils,  Fats,  and  Waxes. — (a)  The  fixed  oils 
and  fats  are  mixtures  of  the  three  bodies,  olein  (liquid),  palmitin 
(semi-solid),  and  stearin  (solid),  or  close  relatives  of  these,  and 
in  addition  usually  small  amounts  of  other  bodies.  Olein, 
palmitin,  and  stearin  are  compounds  of  glyceryl,  C3H5=,  with 
radicles  of  the  various  fatty  acids.  With  alkalies  they  form  soaps 
and  glycerin.  Castile  soap,  for  example,  is  made  by  the  action  of 
sodium  hydroxide  on  olive  oil,  which  is  nearly  pure  olein: 

C3H5(C18H3302)3  +    3NaOH    =  3NaC18H3302  +  C3H6(OH)3 
Olein  Sodium  Castile  soap         Glycerin 

hydroxide 

The  oils  differ  from  the  fats  only  in  the  relative  proportions 
of  these  basal  ingredients,  the  oils  having  more  of  the  olein,  which 
gives  them  a  liquid  consistence  at  ordinary  temperatures,  and  the 
fats  more  of  the  stearin  and  palmitin,  which  make  them  solid  or 
semi-solid. 

The  fats  and  fixed  oils  have  a  greasy  feeling  and  are  non- 
volatile, so  that  they  leave  a  permanent  grease-spot.  They  can- 
not be  distilled,  for  by  heat  they  are  decomposed,  with  the  genera- 
tion of  disagreeable  acrid  vapors  (the  familiar  odor  of  burning 
grease).  They  are  insoluble  in  water  and  alcohol  (except  castor 
oil  and  croton  oil,  which  dissolve  in  alcohol),  and  are  readily 
soluble  in  ether,  chloroform,  and  benzin.  They  are  almost  all 
bland,  non-irritating  substances  with  nutrient  and  emollient 
properties;  but  on  exposure  to  the  air  they  gradually  become 
rancid  by  the  liberation  of  odorous  and  irritating  fatty  acids. 
Linseed  oil  (oleum  lini),  if  exposed  to  the  air  in  thin  layers,  will 
dry  like  varnish,  but  most  of  the  oils  are  of  the  non-drying  type. 
A  few  of  the  fats  and  oils  are  of  animal  origin,  e.  g.,  butter,  lard 
(adeps),  tallow,  suet  (sevum),  and  cod-liver  oil  (oleum  morrhuae) ; 
but  the  majority  are  of  vegetable  origin,  as  almond,  cotton- 
seed, cocoanut,  linseed,  olive  and  peanut  oils,  and  cocoa-butter. 
These  are  found  chiefly  in  seeds  or  in  fruits,  the  best  qualities 
being  usually  obtained  with  the  least  compression  necessary  and 
in  the  cold;  the  poorer  qualities  by  expression  between  heated 
plates.  They  may  also  be  extracted  by  a  suitable  solvent,  such 
as  benzin,  which  is  afterward  removed  by  distillation. 

Cocoa-butter  or  cacao-butter  (oleum  theobromatis)  is  obtained 
from  chocolate-seeds  by  compression  between  hot  or  cold  plates. 


THE   CONSTITUENTS   OF   ORGANIC   DRUGS  31 

The  melted  fat  runs  out  and  congeals  and  is  the  cocoa-butter, 
and  the  residue  constitutes  "cocoa."  This  fat  has  a  very  slight 
odor  and  taste  of  chocolate,  is  firm  and  rather  brittle  at  ordinary 
temperatures,  melts  at  the  temperature  of  the  body,  and  does  not 
readily  become  rancid.  It  is  used  as  a  basis  for  the  manufacture 
of  suppositories,  these  retaining  their  shape  at  ordinary  tempera- 
tures and  quickly  melting  when  inserted  into  a  body  orifice,  such 
as  the  rectum. 

Castor  oil  (oleum  ricini)  and  croton  oil  (oleum  tiglii)  differ 
from  the  other  fixed  oils  in  being  soluble  in  alcohol  and  in  possess- 
ing special  cathartic  properties.  (See  Part  II.)  Castor  oil  is 
sometimes  added  to  alcoholic  hair  lotions  to  prevent  drying  of 
the  scalp  (about  10  minims  to  a  3-ounce  bottle). 

Glycerin  (glycerinum)  is  a  product  of  the  saponification  of 
fats  or  fixed  oils.  (See  Reaction,  page  30.)  It  is  thick  and  viscid, 
has  a  sweet  taste,  mixes  freely  with  water  and  alcohol,  and  has 
great  affinity  for  water.  It  has  extensive  employment  in  phar- 
macy as  a  solvent,  as  a  softening  agent  and  preservative,  and  as 
a  means  for  increasing  the  viscosity  of  liquids,  as  in  the  official 
rhubarb  and  soda  mixture.  Applied  in  concentrated  form  to 
mucous  membranes,  it  is  astringent,  causing  the  superficial  cells 
to  shrink  by  abstraction  of  water.  For  this  reason  it  is  used  as 
an  application  to  a  relaxed  uvula  or  pharynx.  Diluted  with 
water  or  rose-water,  as  in  "rose-water  and  glycerin"  (two  parts 
to  one)  and  in  "calamine  lotion"  (see  Zinc  Carbonate),  it  is  used 
upon  the  skin  as  an  emollient,  serving  to  prevent  the  drying  of  the 
epithelium.  With  lemon-juice  or  rose-water  it  is  also  used  as  an 
application  to  the  dry  tongue  of  fever  patients.  In  mixtures  for 
internal  use  it  serves  as  a  sweetening  agent  and  is  slightly  laxa- 
tive. In  diabetes  it  tends  to  increase  the  glycosuria  (von  Noor- 
den).  For  use  in  the  rectum  as  a  mild  irritant  and  lubricant  it 
may  be  added  to  an  ordinary  enema,  or  used  in  the  form  of  glv- 
cerin  suppositories  (suppositoria  glycerini),  which  hold  95  per 
cent,  of  glycerin.  To  soften  hard  feces,  }4  ounce  (15  c.c.)  may 
be  added  to  half  a  pint  of  soapsuds.  Hertz,  in  "The  Sensibility 
of  the  Alimentary  Canal,"  191 1,  states  that  glycerin  acts  as  an 
irritant  to  the  anal  canal,  but  not  to  the  rectum.  The  glycerites 
are  a  class  of  official  preparations  in  which  glycerin  is  the  sol- 
vent. 

Soaps. — The  soluble  or  detergent  soaps  are  prepared  by  the 
action  of  an  alkali  upon  a  fat  or  oil,  the  potash  soaps  being  soft 
and  those  of  soda  being  hard.  They  contain  glycerin  unless 
this  is  removed  by  washing,  are  soluble  in  alcohol  and  water, 
and  have  an  alkaline  reaction. 

Soap  (sapo),  Castile  or  hard  soap,  is  prepared  by  the  action 


32  PHARMACOLOGY  AND  THERAPEUTICS 

of  sodium  hydroxide  on  olive  oil.  It  is  used  in  the  manufacture 
of  pills,  soap  liniment,  chloroform  liniment,  and  saponified  tooth 
powders.  (For  the  chemic  reaction  see  above,  under  "Fixed 
Oils  and  Fats. ")  Some  time  ago  a  proprietary  house  put  out  a 
preparation  described  as  acid  sodium  oleate.  It  was  extensively 
prescribed  by  physicians,  though  it  was  nothing  but  Castile 
soap  containing  free  fatty  acid. 

Soft  soap  or  green  soap  (sapo  mollis)  is  prepared  from  po- 
tassium hydroxide  and  linseed  oil,  and  is  employed  extensively 
for  cleansing  the  hands  and  skin  preparatory  to  operative  work. 
A  liquefied  form  of  it  is  the  liniment  of  soft  soap  (linimentum 
saponis  mollis),  commonly  called  the  "tincture  of  green  soap," 
made  by  dissolving  soft  soap  in  alcohol  and  adding  oil  of  lavender 
flowers. 

Lipoids  or  Fat  Allies. — Those  of  interest  to  us  are  lecithin 
and  cholesterin.  Lecithin  is  found  in  certain  animal  tissues, 
especially  the  central  nervous  system  and  the  yolk  of  egg.  Of 
the  fatty  substances  of  the  latter,  it  constitutes  about  70  per  cent. 
It  is  a  compound  of  glycerin  and  choline  with  stearic,  palmitic, 
and  phosphoric  acids,  and  is  chemically  a  complex  glycerophos- 
phate.    It  can  be  saponified  by  alkalies.     (See  Phosphorus.) 

Cholesterin,  a  monatomic  alcohol,  C26H43OH,  is  a  crystalline 
body  found  in  all  forms  of  protoplasm,  but  especially  in  brain 
tissue.  It  also  occurs  in  abundance  in  the  yolk  of  egg,  in  milk, 
cream,  and  butter,  and  in  the  bile.  Gall-stones  are  frequently 
the  result  of  its  precipitation  in  the  bile-ducts  or  gall-bladder. 
It  has  been  suggested  in  anemia,  especially  pernicious  anemia, 
in  doses  of  15  grains  (1  gm.)  three  times  a  day;  but  it  is  best 
given  in  the  form  of  milk  and  eggs. 

Lanolin  (adeps  lanae  hydrosus),  the  purified  fat  of  the  wool 
of  sheep,  mixed  with  30  per  cent,  of  water,  is  made  up  of  com- 
pounds of  various  fatty  acids  with  isocholesterin.  It  is  thus  not 
a  glyceryl  fat,  but  a  cholesterin  fat,  and  is  often  classed  with  the 
waxes.  It  is  yellowish- white,  of  soft,  sticky  consistence,  and, 
unlike  the  glyceryl  fats,  cannot  be  saponified  by  boiling  with  an 
aqueous  solution  of  potash.  Its  greatest  interest  for  us  consists 
in  its  power  to  absorb  more  than  its  own  weight  of  water,  which 
makes  it  of  use  as  an  ointment-base  for  substances  in  aqueous 
solution.  It  is  a  secretion  of  the  sebaceous  type,  not  absorbable 
by  the  sheep's  skin.  As  to  its  absorbability  by  the  human  skin 
there  are  conflicting  reports,  but  most  observers  claim  ready 
absorption.  Patschkowski  applied  an  ointment  of  lanolin  and 
potassium  iodide  and  obtained  iodine  in  the  urine  in  half  an  hour. 

The  waxes  are  esters  of  the  fatty  acids  with  hydrocarbon 
radicles  higher  in  the  series  than  glyceryl.     They  are  of  firmer 


THE   CONSTITUENTS    OF    ORGANIC   DRUGS  33 

consistence  than  the  fats,  have  a  higher  melting-point,  and  cannot 
be  saponified  by  boiling  with  an  aqueous  solution  of  potash. 

Beeswax  is  from  the  honey-bee,  and  is  known  in  pharmacy  as 
yellow  wax  (cera  flava).  When  bleached,  it  is  called  white  wax 
(cera  alba).     It  is  chiefly  myricyl  palmitate,  C3oH6i.Ci6H3i02. 

Spermaceti  (cetaceum)  is  obtained  from  the  head  of  the 
sperm-whale,  a  single  whale  yielding  many  barrels.  It  consists 
chiefly  of  cetyl  palmitate,  C16H33.C16H31O0.  The  best  "  cold- 
creams"  contain  spermaceti  and  white  wax;  the  poor  ones  are 
made  of  tallow. 

The  ointments  or  salves  in  common  use  are  prepared  mostly 
from  lard,  suet,  lanolin,  white  wax,  yellow  wax,  spermaceti,  and 
petrolatum  (a  mineral  product). 

The  mineral  oils  do  not  belong  among  the  constituents  of 
organic  drugs,  but  for  convenience  may  be  mentioned  with  the 
other  oils.  They  are  petroleum  products,  are  mixtures  of  hydro- 
carbons, and  are  not  subject  to  rancidity.  The  official  petroleum 
products  are: 

Petroleum  benzin  (benzinum),  a  light,  limpid,  highly  volatile 
and  inflammable  distillate  from  crude  petroleum.  It  is  really 
gasoline  (petrol),  of  specific  gravity  0.638-0.660.  Commercial 
benzin  has  a  higher  specific  gravity.  (Kerosene  oil  is  a  limpid 
petroleum  product  from  which,  for  safety,  the  more  volatile 
hydrocarbons  are  removed  by  distillation.     It  is  not  official.) 

Liquid  paraffin  (liquid  petrolatum)  is  a  much  heavier  and  more 
oily  liquid  than  kerosene.  Trade  names  for  some  of  its  slight 
modifications  are  "liquid  albolene"  and  "liquid  vaseline."  It 
is  used  as  the  vehicle  in  oily  sprays  for  nose  and  throat,  as  the 
agent  of  suspension  of  the  insoluble  salts  of  mercury  for  hypo- 
dermatic use,  as  a  softening  enema  for  hard  feces,  and  by  mouth, 
as  a  mild  laxative;  dose,  1  ounce  (30  c.c.)  two  or  three  times  a  day. 

Petrolatum  (petrolatum)  is  practically  what  we  know  as 
vaseline.     The  Pharmacopoeia  specifies  "without  odor  or  taste." 

White  petrolatum  (petrolatum  album),  a  decolorized  product, 
has  been  marketed  under  the  trade  names  of  "solid  albolene" 
and  "white  vaseline." 

Paraffin  (parafhnum)  is  a  white,  waxy  solid,  the  purified 
residue  left  after  the  liquid  portion  of  the  crude  petroleum  has 
been  removed. 

Petrolatum  and  white  petrolatum  are  of  ointment  consis- 
tence, and  have  the  advantage  in  ointments  of  not  becoming 
rancid.  But  their  value  in  ointments  is  limited,  as  they  are  not 
absorbed  through  the  skin  and  do  not  readily  penetrate  animal 
and  vegetable  parasites.  In  intestinal  or  pancreatic  fistulae, 
vaseline  and  paraffin,  being  non-saponifiable,  have  been  found 
3 


34  PHARMACOLOGY  AND   THERAPEUTICS 

efficient  in  protecting  the  skin  from  erosion ;  while  the  salves  con- 
taining lard  or  other  animal  or  vegetable  fats  become  saponified 
by  the  alkaline  secretions  and  are  useless  or  harmful.  Rovsing 
recommends  vaseline  as  an  injection  into  the  joint  in  dry  arth- 
ritis; and  Wilkie,  the  liquid  vaseline  to  prevent  adhesions  in 
abdominal  surgery.  Kerosene  and  liquid  petrolatum  are  fre- 
quently taken  internally.  They  are  completely  unabsorbed, 
and  serve  merely  to  increase  the  bulk  of  the  intestinal  contents 
and  to  soften  the  feces.  They  retard  the  emptying  of  the 
stomach. 

9.  The  Volatile  Oils. — These  are  the  substances  to  which 
many  plants  owe  their  characteristic  or  essential  odors.  On 
this  account  they  are  often  spoken  of  as  "essential  oils,"  or  as 
the  " essences"  of  plants. 

They  differ  from  the  fixed  oils  in  that — 

1.  They  are  volatile,  therefore  can  be  distilled  and  do  not 
leave  a  permanent  grease  stain. 

2.  They  do  not  form  soaps  with  alkalies. 

3.  They  are  soluble  enough  in  water  to  impart  to  it  their 
odor  and  taste. 

4.  They  do  not  become  rancid,  but  on  exposure  to  light  and 
air  tend  to  oxidize  and  resinify. 

They  mix  freely  in  any  proportions  with  chloroform,  ether, 
and  the  fixed  oils,  and  are  all  soluble  in  absolute  alcohol.  Some, 
like  oil  of  turpentine,  require  several  times  their  own  weight  of 
official  alcohol  for  complete  solution.  They  are  all  mixtures, 
some  of  them  quite  complex. 

Occurrence. — Most  of  them  are  found  in  plants,  and  each  in 
a  definite  part  of  the  plant  from  which  it  is  derived,  e.  g.,  oil  of 
orange  in  the  rind  of  the  fruit;  oil  of  cinnamon  in  the  bark;  oil 
of  rose  in  the  petals.  From  these  parts  they  are  obtained  either 
by  distillation  or  by  means  of  a  suitable  solvent,  such  as  benzin, 
which  is  afterward  removed.  Some  of  the  delicate  essential 
oils  used  in  perfumery,  as  violet  and  heliotrope,  are  obtained  by 
spreading  the  petals  or  flowers  between  wax  plates,  and  after- 
ward separating  the  absorbed  oil  from  the  wax. 

A  few  of  the  volatile  oils  do  not  exist  in  the  living  plant,  and 
are  formed  either  by  the  action  of  ferments  on  glucosides  in  the 
presence  of  water,  as  the  oil  of  bitter  almonds,  or  by  destructive 
distillation.     These  latter  are  known  as  empyreumatic  oils. 

For  convenience,  the  volatile  oils  preexisting  in  the  plant  may 
be  grouped  according  to  their  nature,  and  those  developed  in  the 
plant  part  by  artificial  means  may  be  grouped  according  to  their 
method  of  production. 


THE    CONSTITUENTS    OF    ORGANIC   DRUGS  35 

\  1.  Terpenes,   CxHx   (oils  of  turpentine,  juniper, 

Ietc  ) 
2.   lerpenes  +  stearoptens  (oils  of  lemon,  pepper- 
mint, etc.). 

B.  Not  existing  in  plant  as   (  3.  From  enzyme  action  (oils  of  mustard  and  bitter 
such,     but      developed  \  almond), 

from  plant  constituents:    [  4.  Empyreumatic  (oil  of  cade,  oil  of  tar,  creosote). 

Group  1  is  composed  of  oils  which  are  mixtures  of  terpenes 
(hemiterpenes,  terpenes,  sesquiterpenes,  diterpenes,  pinene, 
etc.,  CioHi6),  the  simplest  hydrocarbon  oils  of  the  aromatic 
series.  Of  all  the  volatile  oils,  they  are  the  least  soluble  in  water 
and  the  most  ready  to  resinify  and  deteriorate.  Examples  are: 
the  oils  of  copaiba,  cubebs,  erigeron,  juniper,  and  turpentine. 
The  last-named  consists  almost  wholly  of  dextrorotary  pinene. 

Group  2  includes  the  mixtures  of  terpenes  which  are  holding 
in  solution  one  or  more  oxygenated  bodies  (of  variable  chemic 
nature,  as  aldehydes,  ketones,  ethers,  acids,  etc.).  The  terpene 
portion  is  known  as  the  eleopten,  and  the  oxygenated  portion  as 
the  stearopten.  The  latter  is  usually  solid,  though  sometimes 
liquid.  It  can  be  separated  from  the  eleopten  by  cold  (as  the 
menthol  of  peppermint  oil)  or  by  fractional  distillation.  It 
is  not  always  readily  soluble  in  95  per  cent,  alcohol.  Examples 
of  stearoptens  which  are  separated  and  used  by  themselves  are 
camphor  and  menthol.  It  is  to  the  stearopten  that  the  charac- 
teristic odor  of  these  oils  is  chiefly  due,  but  the  amount  of  stearop- 
ten present  varies  with  the  different  oils.  For  example,  the  oils 
of  orange  or  lemon  contain  only  a  small  percentage  of  their 
peculiar  stearopten  and  are  nearly  all  eleopten,  while  the  oils 
of  wintergreen  and  birch  are  almost  entirely  composed  of  a  liquid 
stearopten,  which  is  chemically  methyl  salicylate. 

The  oils  of  this  group  are  for  the  most  part  more  soluble  in 
water,  and,  because  of  the  stearopten,  more  agreeable  in  flavor 
than  those  of  Group  1,  so  they  are  largely  used  in  the  manu- 
facture of  the  medicated  waters  and  spirits.  Some  of  them  are 
heavier  than  water,  as  the  oil  of  cinnamon. 

Group  3  contains  those  oils  which  do  not  preexist  in  the  living 
plant,  but  result  from  ferment  action  in  the  presence  of  water. 
The  official  ones  are  the  oil  of  bitter  almond  and  the  volatile  oil 
of  mustard.  (For  the  reactions  in  the  development  of  these 
oils  see  under  Glucosides  above.) 

Group  4  contains  the  empyreumatic  oils,  those  which  do  not 
preexist  in  the  plant,  but  result  from  its  destructive  distillation. 
The  official  ones  are :  Oil  of  cade  (oleum  cadinum) ,  from  juniper 
wood,  and  oil  of  tar  (oleum  picis  liquidae),  from  the  wood  of  Pinus 
palustris  and  other  species  of  pine.     Both  have  a  tarry  odor, 


36  PHARMACOLOGY  AND   THERAPEUTICS 

and  are  added  to  ointments  for  the  treatment  of  chronic  skin 
diseases.  The  syrup  of  tar  (syrupus  picis  liquidae),  in  dose  of 
15  minims  (1  c.c),  is  also  used  as  an  expectorant. 

Creosote  is  a  mixture  of  phenols  and  phenol  derivatives, 
obtained  during  the  distillation  of  wood-tar,  and  has  some  of  the 
properties  of  a  volatile  oil.  The  beechwood  creosote  is  considered 
best  for  medicinal  purposes. 

The  volatile  oils  have  marked  pharmacologic  actions,  but 
do  not  belong  to  a  single  pharmacologic  group.  Their  action 
will  be  considered  in  Part  II. 

10.  The  resins  are  all,  or  nearly  all,  mixtures  of  several 
different  substances.  They  are  an  ill-defined  group,  forming 
amorphous  masses  which  have  a  conchoidal  shining  fracture. 
They  are  insoluble  in  water  and  soluble  in  ether,  chloroform, 
and  the  volatile  oils.  Many,  but  not  all,  of  them  are  soluble  in 
alcohol,  and  most  of  them  dissolve  in  alkali  with  the  formation 
of  a  non-detergent  resin-soap,  which  is  miscible  with  water. 
Their  composition  is  still  a  subject  of  study.  Some  of  them,  and 
perhaps  all  of  them,  are  formed  by  the  oxidation  of  volatile  oils, 
in  association  with  which  in  the  plant  they  mostly  occur.  Com- 
mon rosin,  and  the  resins  of  guaiac,  jalap,  podophyllum,  and 
scammony,  are  official  resins. 

1 1 .  The  oleoresins  are  the  natural  plant  exudates  which  con- 
tain both  volatile  oil  and  resin.  Balsam  of  copaiba,  Canada 
balsam,  and  crude  turpentine  are  examples,  common  rosin  and 
oil  of  turpentine  being  the  components  of  crude  turpentine. 
(These  natural  oleoresins  must  be  distinguished  from  the  pharma- 
ceutic oleoresins,  which  are  artificial  ethereal  extracts  of  oily 
and  resinous  drugs,  i.  e.,  extracts  made  with  ether.) 

12.  The  gum  resins  are  generally , oleoresins  in  natural  ad- 
mixture with  gum.  They  are  obtained  by  the  evaporation  of  the 
milky  juices  of  certain  plants.  On  rubbing  a  gum  resin  with 
water  the  gum  dissolves,  and  with  the  oil  and  resin  forms  a  milky 
emulsion.     Asafetida  and  gamboge  are  examples. 

13.  The  balsams  are  resinous  or  oleoresinous  exudates  which 
contain  benzoic  or  cinnamic  acid,  or  both.  These  latter  impart 
a  " balsamic"  odor.  Benzoin,  storax,  balsam  of  Tolu,  and 
balsam  of  Peru  are  official  examples.  Many  fragrant  substances 
are  incorrectly  called  "balsams,"  e.  g.,  balsam  of  copaiba  and 
Canada  balsam,  both  of  which  are  oleoresins.  In  some  instances 
the  resins,  oleoresins,  gum  resins,  and  balsams  are  the  only 
commercial  representatives  of  their  respective  plants. 


PHARMACEUTIC   PREPARATIONS  37 

SPECIAL   ANIMAL  DERIVATIVES 

Gelatin  (gelatinum)  is  obtained  by  acting  with  boiling  water 
upon  certain  animal  tissues,  as  the  skin,  ligaments,  and  bones, 
and  allowing  the  solution  to  dry  in  the  air.  It  may  be  obtained 
in  thin,  transparent  sheets  which  are  permanent  if  dry,  but  when 
moist,  readily  putrefy.  It  is  soluble  in  boiling  water,  and  in  the 
proportion  of  i  part  of  gelatin  to  50  of  water  forms  a  jelly  on 
cooling.  In  cold  water  it  does  not  dissolve,  though  it  absorbs 
water  and  swells.  It  is  precipitated  from  solution  by  tannic 
acid  as  a  tough,  leathery,  insoluble  mass,  a  matter  of  importance 
in  the  administration  of  capsules  and  of  gelatin-coated  pills.  Be- 
sides its  uses  in  pharmacy  and  as  a  food,  a  sterilized  i  per  cent, 
solution  in  amounts  up  to  ioo  c.c.  per  day  has  been  employed  by 
hypodermoclysis  and  intravenously  in  hemorrhage  and  aneurysm 
to  increase  the  coagulability  of  the  blood.  It  is  a  protein  food 
from  which  indol  is  not  formed,  hence  may  be  valuable  in  in- 
testinal putrefaction.  Glycerinated  gelatin,  a  compound  of  equal 
parts  of  gelatin  and  glycerin,  is  a  rubbery  mass,  used  as  a  basis 
for  vaginal  suppositories  and  urethral  bougies.  It  melts  at  the 
temperature  of  the  body. 

Keratin  is  obtained  from  horn  by  dissolving  out  the  albumin- 
ous matter  with  artificial  digestion,  and  macerating  the  residue 
in  ammonia.  It  is  soluble  in  alkalies  and  insoluble  in  acids,  and 
is  employed  as  a  coating  for  pills  and  capsules  which  it  is  desired 
to  have  pass  through  the  stomach  without  action — the  so-called 
"enteric"  pills.  Theoretically,  if  the  pills  are  given  after  meals, 
the  coating  should  not  dissolve  in  the  stomach,  and  the  medicinal 
agents  should  be  set  free  only  when  the  pills  reach  the  alkaline 
intestinal  contents.  As  a  matter  of  fact,  however,  commercial 
keratin  is  not  always  proof  against  disintegration  in  the  stomach, 
and  its  coating  must  be  considered  unreliable. 

PHARMACEUTIC  PREPARATIONS 

The  chemicals  and  the  various  mineral,  plant,  or  animal 
crude  drugs  may  be  employed  in  medicine  as  such  without  change, 
e.  g.,  sodium  bicarbonate  or  cod-liver  oil,  or  powdered  digitalis 
leaves;  or  they  may  be  made  into  pharmaceutic  preparations, 
as  the  rhubarb  and  soda  mixture,  the  emulsion  of  cod-liver  oil, 
or  the  tincture  of  digitalis. 

Pharmaceutic  preparations  are  the  prepared  forms  into  which 
drugs  are  made  for  convenient  employment  in  medicine.  It  is 
not  convenient,  for  instance,  to  administer  cinchona  in  the  form 
of  cinchona  bark.  It  would  be  a  disagreeable  task  for  a  patient 
to  chew  the  bitter  bark,  and  difficult,  because  of  the  inert  matter 


38  PHARMACOLOGY  AND   THERAPEUTICS 

present,  to  obtain  in  this  way  the  full  physiologic  activity  of  the 
drug.  But  the  tincture  of  cinchona,  a  pharmaceutic  preparation, 
represents  the  full  physiologic  activity  of  the  drug,  because  the 
active  principles  are  held  in  solution,  and  it  is  easily  administered. 

In  the  preparation  the  drug  or  drugs — (a)  may  remain  un- 
changed, as  in  the  emulsion  of  cod-liver  oil,  rhubarb  pills,  or 
powder  of  ipecac  and  opium  (Dover's  powder);  or  (b)  may  be 
changed  by  chemic  reaction,  as  in  Fowler's  solution  or  Basham's 
mixture;  or  (c)  may  be  made  to  yield  their  active  constituents 
to  a  suitable  solvent,  as  in  preparations  made  by  extraction. 
Preparations,  too,  may  be  employed  in  the  manufacture  of  other 
preparations,  as  cinnamon  water  in  making  chalk  mixture,  and 
the  extract  of  belladonna  in  making  a  belladonna  plaster. 

Extraction  is  the  process  of  obtaining  the  active  constituents 
of  an  animal  or  vegetable  drug  by  means  of  a  suitable  solvent. 
By  this  process  the  inert  woody  fiber,  cellulose,  and  other  matters 
that  are  insoluble  in  the  solvent  employed  are  left  behind,  so 
that  only  the  soluble  matters  of  the  crude  drug  appear  in  the 
preparation.  In  extraction  the  solvent  is  known  as  the  men- 
struum, and  this  differs  with  the  different  drugs  or  types  of 
preparation.  It  may  be  water,  alcohol,  alcohol  and  water, 
alcohol  and  glycerin,  glycerin,  wine,  acetic  acid,  ether,  chloro- 
form, etc.     Official  preparations  made  by  extraction  are: 

A.  With  aqueous  solvent — infusions  and  decoctions. 

B.  With  alcoholic  solvent  (in  most  instances) — extracts,  fluid- 

extracts,  and  tinctures. 

C.  With  wine — wines. 

D.  With  diluted  acetic  acid — vinegars. 

E.  With  ether — oleoresins. 

Preparations  made  by  extraction  represent  the  activity  of  the 
crude  drug,  but  in  addition  to  the  active  principles,  always  con- 
tain more  or  less  physiologically  inert  matter  which  has  gone  into 
the  solution.  Such  inert  matter  is  known  as  the  "extractive," 
and  it  consists  of  such  substances  as  fat,  wax,  oil,  tannin,  chloro- 
phyll, etc.  Such  "extractive"  is  mostly  colloidal  in  nature, 
and  has  a  tendency  to  retard  the  absorption  and  the  activity  of 
the  active  constituents. 

Percentage  Strength  of  Liquids. — There  are  two  types  of 
percentage  liquids — the  chemic  and  the  pharmaceutic.  The 
chemic  percentage  liquid  deals  only  with  weight,  as  chemic  reac- 
tions involve  relative  weights  regardless  of  volume.  To  make  a 
20  per  cent,  chemic  solution,  20  grams  of  the  substance  to  be 
dissolved  are  mixed  with  80  grams  of  solvent;  therefore,  100 
grams  (weighed)  of  the  solution  would  furnish  20  grams  of  the 
contained    ingredient.     In    the   pharmaceutic   percentage   liquid, 


PHARMACEUTIC   PREPARATIONS  39 

however,  solids  are  weighed  and  liquids  measured,  so  that  in 
making  a  20  per  cent,  pharmaceutic  solution  20  grams  of  the 
substance  to  be  dissolved  are  mixed  with  enough  solvent  to  make 
the  total  measure  100  c.c.  Of  such  solution,  100  c.c.  (measured) 
will  contain  20  grams  of  the  drug.  In  the  practice  of  medicine, 
liquid  remedies  are  always  administered  by  measure,  for  one  can- 
not carry  scales  to  the  bedside;  therefore  the  United  States 
Pharmacopoeia  adopts  the  pharmaceutic  percentage  liquid,  so 
that  a  given  measure  will  contain  an  easily  calculated  amount  of 
each  essential  ingredient.  The  volumetric  solutions  used  in 
chemic  analysis  are  made  on  the  same  plan.  By  this  method  a 
very  soluble  chemical,  such  as  potassium  iodide,  may  be  had 
in  100  per  cent,  solution. 

As  an  illustrative  example  of  the  difference  between  the  chemic 
and  the  pharmaceutic  percentage  liquid,  let  us  take  a  10  per  cent, 
solution  of  cocaine  hydrochloride  in  normal  saline.  In  the 
pharmaceutic  solution,  10  grams  of  the  cocaine  salt  are  dissolved 
in  a  quantity  of  normal  saline,  and  sufficient  normal  saline  added 
to  make  the  finished  solution  measure  100  c.c.  Of  this  solution, 
a  measure  of  10  c.c.  will  give  1  gram  of  the  cocaine  salt,  a  measure 
of  1  c.c.  will  give  0.1  gram,  and  there  is  a  simple  relation  between 
the  measure  of  the  solution  and  the  amount  of  cocaine  it  contains. 
In  the  chemic  solution  10  grams  of  the  cocaine  salt  are  dissolved 
in  90  grams  of  the  normal  saline,  so  that  if  one  wished  to  use  0.1 
gram  of  cocaine  hydrochloride,  one  could  not  get  it  by  measure, 
since  there  is  no  easily  calculated  relation  between  the  measure 
of  the  liquid  and  the  weight  of  its  dissolved  constituents;  there- 
fore, one  would  have  to  weigh  off  1  gram  of  the  solution.  Such 
weighing  cannot  be  done  in  practice,  therefore  the  chemic  percent- 
age method  is  not  suitable  for  pharmaceutic  liquids. 

To  conform  with  the  idea  of  weighing  solids  and  measuring 
liquids  the  Pharmacopoeia  specifies  that  in  liquid  preparations 
made  by  extraction  a  definite  weight  of  the  drug  shall  be  employed 
in  making  a  definite  volume  of  the  finished  preparation.  Hence 
these  preparations  have  a  definite  relation  in  strength  to  the  drug 
from  which  they  are  made,  for  the  active  ingredients  of  a  definite 
weight  of  the  drug  are  in  the  solution.  The  strengths  of  pharma- 
ceutic preparations  are  indicated  by  the  amount  of  drug  used  in 
their  making,  whether  the  drugs  themselves  are  in  the  finished 
preparation  or  only  their  extracted  constituents.  Thus  a  measure 
of  100  c.c.  of  the  tincture  of  digitalis  represents  the  medicinal 
activity  of  10  grams  of  digitalis  leaves;  the  tincture  is,  therefore, 
of  10  per  cent,  strength.  A  measure  of  100  c.c.  of  the  fluid- 
extract  of  cascara  represents  the  medicinal  activity  of  100  grams 
of  cascara,  hence  the  fluidextract  is  of  100  per  cent,  strength. 


40  PHARMACOLOGY  AND   THERAPEUTICS 

Pharmaceutic  preparations  are  simple  or  compound.  The 
simple  preparations  represent  the  activity  of  one  drug  only;  the 
compound  preparations,  the  activity  of  more  than  one  drug. 
For  example,  rhubarb  pills  have  rhubarb  as  the  only  constituent, 
while  compound  rhubarb  pills  contain  rhubarb,  aloes,  myrrh, 
and  oil  of  peppermint. 

Nomenclature. — The  simple  preparations  are  given  simply 
the  name  of  the  drug  prefixed  by  the  name  of  the  kind  of  prepara- 
tion, as:  Syrup  of  ginger  (syrupus  zingiberis),  infusion  of  digitalis 
(inf usum  digitalis) .  The  compound  preparations  have  two  types 
of  nomenclature.  If  the  active  drugs  are  only  two  in  number, 
or  in  some  cases  three,  all  are  mentioned  in  the  name,  as:  Pills 
of  aloes  and  iron  (pilula  aloes  et  ferri),  elixir  of  the  phosphates 
of  iron,  quinine,  and  strychnine  (elixir  ferri,  quininae  et  strych- 
ninae  phosphatum).  If  the  important  drugs  are  several  in  num- 
ber, especially  if  one  overshadows  the  others  in  importance,  only 
one  drug  is  named,  and  the  name  of  the  class  of  preparation  is 
modified  by  the  term  compound.  Examples  are:  Compound 
tincture  of  cinchona  (tinctura  cinchonas  composita),  which  is 
made  of  cinchona,  serpentaria,  and  bitter-orange  peel:  compound 
licorice  powder  (pulvis  glycyrrhizae  compositus),  which  contains 
glycyrrhiza,  senna,  and  sulphur;  and  compound  rhubarb  pills, 
mentioned  above. 

A  few  compound  preparations  of  this  kind  do  not  bear  a  drug 
name,  but  the  name  which  indicates  their  use  in  medicine,  as 
compound  cathartic  pills  (pilulae  catharticae  compositae). 

DEFINITIONS  OF  THE  KINDS  OF  PHARMACEUTIC  PREPARATIONS 
IN  COMMON  USE 

Aqueous  Liquids. — i.  Water  (Aqua). — A  weak  aqueous  solu- 
tion of  one  or  more  volatile  substances  (e.  g.,  peppermint  or 
cinnamon  water,  chlorine  water). 

2.  Solution  (Liquor). — An  aqueous  solution  of  one  or  more 
non- volatile  chemic  substances  (Fowler's  solution). 

3.  Mixture  (Mistura). — An  aqueous  liquid  containing  in- 
soluble material  (rhubarb  and  soda  mixture).  It  requires  the 
label,  "Shake  before  using." 

4.  Syrup  (Syrupus). — A  dense  aqueous  solution  of  sugar  with 
or  without  medicinal  or  flavoring  substances  (syrup  of  ipecac) . 

5.  Mucilage  (Mucilago). — An  adhesive  aqueous  liquid  or 
paste  made  with  gum  (liquid — acacia;   paste — tragacanth). 

6.  Infusion  (Infusum). — A  liquid  obtained  by  steeping  a 
vegetable  drug  in  water  and  then  straining.  The  water  may  be 
cold,  warm,  or  hot,  but  the  drug  is  not  subjected  to  boiling. 

7.  Decoction  (Decoctum). — A  liquid  made  by  boiling  a  vege- 
table drug  with  water,  then  straining. 


PHARMACEUTIC   PREPARATIONS  4 1 

8.  Juice  (Succus). — The  juice  expressed  from  parts  of  fresh 
plants  (" fresh"  meaning  "undried");  the  only  official  juice  is 
limonis  succus  (lemon-juice).  Alcohol  may  be  added  as  a  pre- 
servative. 

Alcoholic  Liquids. — i.  Fluidextract  (Fluidextractum). — An 
alcoholic  or  hydro-alcoholic  liquid  preparation  made  by  extrac- 
tion, and  representing  the  drug  volume  for  weight;  i.  e.,  i  c.c. 
of  the  fluidextract  represents  the  strength  of  i  gram  of  the  drug. 

2.  Tincture  (Tinctura). — An  alcoholic  or  hydro-alcoholic 
liquid  preparation  made  by  extraction  and  of  a  strength  less  than 
that  of  the  drug;  i.  e.,  tinctures  are  of  the  same  nature  as  fluid- 
extracts,  but  weaker.  A  few  simple  alcoholic  solutions  are  in- 
correctly called  tinctures,  e.  g.,  tincture  of  ferric  chloride,  tincture 
of  iodine. 

3.  Wine  (Vinum). — Like  a  tincture  or  solution,  but  made  with 
white  wine  and  alcohol  as  the  menstruum  (bitter  wine  of  iron). 

4.  Elixir  (Elixir). — A  sweetened,  aromatic,  hydro-alcoholic 
liquid  (aromatic  elixir). 

5.  Spirit  (Spiritus). — A  simple  solution  of  one  or  more  volatile 
substances  in  alcohol  (spirit  of  chloroform). 

Miscellaneous  Liquids. — i.  Vinegar  (Acetum). — Made  like 
a  tincture,  but  with  diluted  acetic  acid  as  the  menstruum  (the 
vinegars  of  opium  and  of  squill  are  the  only  ones  official) . 

2.  Emulsion  (Emulsum). — A  milk-like  preparation  in  which 
an  oil  or  resin  is  finely  divided  and  rendered  miscible  with  water 
by  means  of  some  viscous  or  adhesive  substance.  Emulsions 
are:  (a)  Natural,  as  in  egg-yolk  and  milk,  (b)  Gum  resin,  as  in 
emulsum  asafcetidae;  the  drug  contains  gum,  oil  and  resin,  and 
on  rubbing  with  water  makes  an  emulsion.  (c)  Artificial, 
in  which  the  adhesive  must  be  added,  as  emulsion  of  cod-liver  oil. 

3.  Honey  (Mel). — A  liquid  or  semi-liquid  mixture  of  a  drug 
with  honey  (honey  of  rose). 

4.  Oleoresin  (Oleoresina) . — A  semi-liquid  ethereal  extract 
of  a  drug  which  contains  oil  and  resin.  The  oleoresin  contains 
the  ether-soluble  constituents  of  the  drug,  the  ether  being  evap- 
orated off.  It  is  of  greater  strength  than  the  drug  itself  (oleoresin 
of  male  fern). 

5.  Glycerite  (Glyceritum) . — A  liquid  or  semi-solid  solution  in 
glycerin  (glycerite  of  boroglycerin) . 

6.  Liniment  (Linimentum). — An  oily  or  alcoholic  solution  or 
mixture  to  be  applied  to  the  skin.  (A  lotion  is  an  aqueous  liquid 
for  application  to  the  skin.     There  are  no  official  lotions.) 

7.  Collodion  (Collodium). — A  solution  of  a  medicinal  sub- 
stance in  collodion  (cantharidal  collodion). 

Solids  and  Semi-solids. — i.  Extract  (Extractum). — A  prepa- 
ration of  dry  or  plastic  consistence,  made  by  extracting  a  drug 


42  PHARMACOLOGY  AND  THERAPEUTICS 

with  a  solvent,  and  then  removing  the  solvent  by  evaporation. 
An  extract  is  of  greater  strength  than  the  crude  drug.  Most 
extracts  are  from  5  to  10  times  as  strong  as  the  drug  from  which 
they  are  made  (extract  of  belladonna). 

2.  Powder  (Pulvis). — A  dry  powdery  mixture  of  drugs 
(powder  of  ipecac  and  opium) . 

3.  Trituration  (Trituratio) . — A  powdery  mixture  of  a  drug 
with  sugar  of  milk.  The  only  official  trituration  is  trituratio 
elaterini,  of  10  per  cent,  strength. 

4.  Mass  (Massa). — A  plastic  mixture  for  division  into  a  num- 
ber of  equal  objects,  such  as  pills,  troches,  etc.,  and  usually  ob- 
tained by  incorporating  drugs  with  an  adhesive  substance. 

5.  Pill  (Pilula). — A  rounded  or  oval  body  of  size  to  be  readily 
swallowed,  and  made  of  cohesive  drugs  or  drugs  incorporated 
with  an  adhesive  substance.  Pills  may  be  coated  with  sugar, 
gelatin,  silver,  keratin,  or  salol.  The  coating  may  be  white, 
pink,  chocolate-colored,  etc. 

6.  Troche  (Trochiscus) . — A  flat  body,  rounded  or  lozenge- 
shaped,  intended  to  be  dissolved  slowly  in  the  mouth.  It  con- 
tains the  medicinal  substance,  and  in  addition  sugar,  flavoring 
and  adhesive  material  (troches  of  ammonium  chloride). 

7.  Compressed  Tablet. — A  solid  body  made  by  the  compression 
of  a  powdered  drug  or  mixture  of  drugs  in  a  suitable  mold. 
With  insoluble  powders  the  hard  compression  retards  disinte- 
gration. 

8.  Tablet  Triturate. — A  solid  body  made  of  drugs  triturated 
with  sugar  of  milk,  and  molded  with  the  aid  of  moisture.  They 
disintegrate  as  the  sugar  of  milk  dissolves. 

g.  Confection  (Confectio). — A  pleasant-tasting  preparation 
made  by  mixing  medicinal  powders  and  aromatics  with  syrup 
or  honey  (confection  of  senna) . 

10.  Granular  Effervescent  Salt  (Sal  Granulatus  Effervescens) . 
— A  preparation  made  by  adding  sodium  bicarbonate  and  citric 
or  tartaric  acid  to  the  drug,  moistening  with  alcohol,  and  passing 
through  a  coarse  sieve  to  form  granules.  It  is  added  to  water  and 
drunk  while  effervescing  or  later  (effervescent  sodium  phosphate) . 

11.  Paper  (Charta). — A  sheet  of  paper  impregnated  with  a 
medicinal  substance  (niter  paper),  or  bearing  it  in  a  state  of  fine 
subdivision  (mustard  paper). 

12.  Plaster  (Emplastrum). — A  solid  mixture  which  becomes 
plastic  and  adhesive  on  warming;  it  is  spread  in  a  thin  layer  over 
muslin,  moleskin,  etc.,  for  application  to  the  skin. 

1  j.  Poultice  (Cataplasma). — A  soft,  usually  hot  and  moist 
paste  for  external  application. 

14.  Ointment  (Unguentum) . — A  soft,  fatty  (unctuous)  pre- 
paration which  on  rubbing  melts  at  the  temperature  of  the  body. 


WEIGHTS   AND   MEASURES 


43 


75.  Cerate  (Ceratum). — An  unctuous  mixture  of  firmer  con- 
sistence and  higher  melting-point  than  an  ointment. 

16.  Oleate  (Oleatum). — A  semi-solid  solution  of  metallic 
salts  or  alkaloids  in  oleic  acid.     It  is  for  external  use. 

17.  Suppository  (Suppositorium) . — A  solid  which  retains 
its  shape  at  normal  temperature  but  readily  fuses  when  inserted 
into  a  body-orifice.  Suppositories  are  usually  made  with  a  basis 
of  cocoa-butter  and  are — (a)  Rectal,  cone-shaped,  weight  2  gm. 
(b)  Urethral,  thin,  pencil-shaped,  weight  2  to  4  gm.  (c)  Vaginal, 
globular  or  elliptic,  weight  4  gm.  Urethral  and  vaginal  sup- 
positories are  sometimes  made  of  glycerinated  gelatin. 


WEIGHTS  AND  MEASURES 

A.  Metric 

Approximate 
Weight  Written  Equivalent 

i  milligram  (mg.) 0.001  ^  grain 

10  milligrams  =  1  centigram  (eg.) 0.01  £  grain 

10  centigrams  =  1  decigram  (dg.) 0.1  i|  grains 

10  decigrams  =  1  gram  (gm.) 1.0  15  grains 

1000  grams  =  1  kilogram  (kilo.) igoo.o  2±  pounds 

Volume 

1  cubic  centimeter  (c.c.) 1.0  15  minims 

(1  c.c.  of  water  weighs  1  gm.) 

1000  cubic  centimeters  =  1  liter  (L.) 1000.0  34  fluidounces 

Length 

1  millimeter  (mm.) 2^  inch 

10  millimeters  =  i  centimeter  (cm.) f  inch 

10  centimeters  =  1  decimeter  (dm.) 4  inches 

10  decimeters  =  1  meter  (M.) 40  inches 

B.  Apothecaries 

Approximate 
Weight  (Troy  Weight)  Equivalent 

1  grain  (gr.) 0.065  gm- 

10  grains 0.7  gm. 

20  grains  =  1  scruple  O) 1.3  gm. 

3  scruples  =  1  dram  ( 5 ) 4.0  gm. 

8  drams  =  1  ounce  ( 3 ) 30.0  gm. 

12  ounces  =  i  pound  (lb) 372.0  gm. 

Volume 

1  minim  (ttjj) 0.06  c.c. 

60  minims  =  1  dram  (  5 ) 4-o  c.c. 

S  drams  =  1  ounce  ( 5 ) 30.0  c.c. 

16  ounces  =  1  pint  (O) 475 -o  c.c. 

2  pints  =  1  quart  (Oij) 9S°°  c-c- 

8  pints  =  1  gallon  (Cong.) 

(1  gill  =  4  fluidounces.) 

Length 

1  inch  (in.) 2.5        cm. 

Noteworthy  Terms 

1  ounce  avoirdupois , 437-5        grains 

1  ounce  troy 480.0        grains 

1  fluidounce  of  water  (the  standard  of  volume) 455-7        grains 


44  PHARMACOLOGY  AND   THERAPEUTICS 

Approximate 
Noteworthy  Terms  Equivalent 

i  pound  avoirdupois  is 7000.0        grains 

1  pound  troy  is 5760.0        grains 

1  minim  of  water  weighs  -5I?'7   grains =0.95  grain. 

15  grains  of  water  =16  minims;  one  grain  of  water  measures 

1.05  minims. 
An  imperial  pint  is  20  ounces;  a  United  States  pint  is  16  ounces. 

EXACT  EQUIVALENTS  OF  METRIC  AND  APOTHECARIES'  WEIGHTS 
AND   MEASURES  ACCORDING  TO  THE  U.  S.  PHARMACOPEIA 

Volume 

1  c.c 16.23      minims 

1  liter  (1000  c.c.) ' 33.8        oz. 

1  minim  (njf) 0.061  c.c. 

1  fluidram  (3) 3-696  c.c. 

1  fluidounce  (o) 29.57  c.c. 

1  pint   (O) 473-i8  c.c. 

Weight 

1  milligram,  0.001  (mg.) 0.0154  grain 

1  centigram,  0.01  (eg.) 0.1543  grain 

1  decigram,  0.1  (dg.) 1.543    grains 

1  gram,  1.0  (gm.) 15-43.24  grains 

30  grams,  30.0 462.9        grains 

31  grams 478-4        grains 

1  grain  (gr.) .- '. 0.065    gm. 

10  grains 0.648  gm. 

15  grains 0.972  gm. 

1  scruple 1.296  gm. 

1  dram  ( 3) -  - ^ 3-89  gm. 

1  ounce  troy  (5) 31.1  gm. 

1  ounce  avoirdupois 28.35  gm- 


ACTIVE  PRINCIPLES  AND  ASSAY  PROCESSES 

As  might  be  expected  from  the  different  conditions  under 
which  plants  grow,  the  different  methods  of  collecting,  drying, 
and  preserving  drugs,  the  effects  of  age  on  the  drug,  etc.,  crude 
drugs  vary  in  strength.  On  this  account  the  use  of  active  con- 
stituents by  themselves  has  much  to  commend  it,  e.  g.,  quinine 
in  preference  to  cinchona,  strychnine  in  preference  to  nux  vomica, 
resin  of  podophyllum  in  preference  to  podophyllum.  These 
substances  tend  also  to  be  more  readily  absorbed  when  thus 
separated  from  the  extractive  matter  of  the  crude  drug.  But 
in  many  instances  it  is  impossible  or  too  expensive  to  isolate  the 
active  ingredients  in  pure  form,  or  there  is  a  preference  for  the 
combinations  or  mixtures  as  they  occur  in  nature,  so  pharma- 
ceutic preparations,  and  even  the  powdered  crude  drugs,  are 
much  prescribed,  even  though  their  active  principles  are  available. 

This  being  the  case,  it  is  a  matter  of  great  importance  that  some 
of  the  more  potent  of  these  drugs  and  preparations  are  standard- 
ized by  the  Pharmacopoeia  to  contain  a  definite  percentage  of  the 
active  ingredients.     For  instance,  when  assayed  by  the  process 


THE   PHARMACOPCEIA  45 

specified  in  the  Pharmacopoeia,  mix  vomica  must  yield  not  less 
than  1.25  per  cent,  of  strychnine;  jalap,  not  less  than  8  per  cent, 
of  resin;  the  tincture  of  opium,  1.2  to  1.25  per  cent,  of  morphine. 
These  are  known  as  assayed  drugs  or  preparations. 

An  assay  process  is  a  process  by  which  the  strength  of  a  sub- 
stance or  preparation  is  determined.  There  are  three  kinds  of 
assay  processes  for  drug  preparations,  viz.,  chemic  or  volumetric, 
pharmaceutic  or  gravimetric,  and  physiologic.  The  last-named 
type  of  assay  has  been  devised  for  some  of  the  drugs  whose  active 
principles  are  not  readily  isolated.  For  digitalis,  for  example, 
one  assay  process  ascertains  the  amount  of  digitalis  necessary 
to  bring  into  systolic  standstill  the  heart  of  a  frog  of  definite 
weight  and  of  a  certain  species  and  sex.  Physiologic  assays  are 
not  recognized  by  the  Pharmacopoeia,  but  for  some  drugs  the 
physiologic  effect  is  the  only  available  criterion  of  strength,  so 
they  are  employed  by  the  best  manufacturing  firms. 

THE  PHARMACOPCEIA 

The  Pharmacopoeia  is  a  book  which  defines  and  standardizes 
certain  drugs  and  their  preparations.  Its  aim  is  to  establish 
defmiteness  for  a  selected  number  of  those  in  extensive  use  by 
physicians.  A  number  of  the  more  enlightened  nations  have 
pharmacopeias,  so  there  are  the  British  Pharmacopoeia,  the 
German,  the  Swiss,  the  Japanese,  etc.  For  us,  "The  Pharma- 
copoeia "  is  the  United  States  Pharmacopoeia  (written  "U.S.  P."). 
Its  drugs  and  preparations  are  spoken  of  as  official.  By  the  Pure 
Food  and  Drugs  Act  the  National  Formulary  preparations  have 
also  official  recognition.  The  official  preparations  are,  therefore, 
the  ones  that  are  standardized;  hence  they  are  the  preparations 
that  can  be  obtained  of  uniform  strength  throughout  the  United 
States;  and  they  are,  for  the  most  part,  the  forms  in  which  reme- 
dies can  be  readily  supplied  by  the  pharmacist.  Hence,  the 
official  preparations  are  the  forms  to  be  preferred  by  the  physician 
in  prescribing. 

To  illustrate  the  character  of  the  Pharmacopoeia,  let  us  take 
the  drug  strophanthus  and  its  tincture.  "  Strophanthus  "  is  de- 
fined as  "the  ripe  seed  of  Strophanthus  Kombe,  deprived  of  its 
long  awn."  The  seeds  of  other  species  of  strophanthus  can  be 
procured,  but  the  pharmacist  must  not  employ  any  but  those  of 
the  species  Strophanthus  Kombe,  and  he  must  first  remove  its 
long  awn,  a  spear-like  projection  at  the  apex  of  the  seed  which 
contains  none  of  the  medicinal  ingredient.  For  the  tincture  of 
strophanthus  the  Pharmacopoeia  directs  that  10  grams  of  stro- 
phanthus shall  be  taken  to  make  ioo  c.c.  of  the  tincture,  i.  e., 


46  PHARMACOLOGY  AND   THERAPEUTICS 

it  shall  be  of  10  per  cent,  strength,  and  it  must  be  made  with  a 
certain  specified  menstruum.  Therefore,  when  the  tincture  of 
strophanthus  is  prescribed,  since  it  is  an  official  preparation,  the 
pharmacist  is  not  entitled  to  dispense  a  tincture  of  any  other 
strength  or  method  of  manufacture.  On  the  contrary,  if  a 
physician  prescribes  an  unofficial  preparation,  the  pharmacist 
may  dispense  one  of  any  arbitrary  strength  and  made  by  any 
method  convenient,  and  the  physician  is  left  in  uncertainty  about 
what  his  patient  is  getting. 

The  United  States  Pharmacopoeia  gives  information,  also, 
about  specific  gravity,  melting-point,  solubilities,  tests  of  identity, 
tests  for  impurities  or  adulterants,  the  average  dose,  etc.  It  is. 
therefore,  an  official  formulary  and  book  of  standards,  and  is  a 
working  guide  and  dictator  for  the  supplier  of  drugs,  the  manu- 
facturer of  preparations,  and  the  pharmacist.  It  is  not  in  any 
sense  a  book  to  be  memorized  by  the  medical  student;  but  the 
choice  of  its  preparations  in  prescribing  favors  accurate  thera- 
peutics. 

The  Pharmacopoeia  is  controlled  and  published  by  the  Na- 
tional Convention  for  Revising  the  Pharmacopoeia,  a  gathering 
of  delegates  from  the  various  medical  and  pharmaceutic  colleges 
and  state  and  national  societies,  and  from  the  Army,  Navy, 
and  Marine-Hospital  Service.  This  Revision  Convention,  meets 
every  ten  years  (1890,  1900,  1910,  etc.)  at  Washington,  D.  C, 
to  determine  the  principles  to  govern  the  next  revision.  It 
also  appoints  a  Committee  of  Revision  to  carry  out  the  details 
of  the  revision,  and  administrative  officers  to  issue  the  new  edi- 
tion when  it  is  ready.  Three  or  four  years  are  then  spent  by  the 
Committee  of  Revision  in  research  and  in  the  compilation  of  the 
revised  book,  which  becomes  official  on  a  fixed  date  after  it  is 
issued.  It  is  known  as  the  Pharmacopoeia  of  1890,  or  1900.  etc., 
the  year  of  the  Pharmacopceial  Convention.  The  present  Phar- 
macopoeia is  the  Pharmacopoeia  or  revision  of  1900;  it  became 
official  on  September  1,  1905.  If  a  physician  wishes  to  prescribe 
the  formula  of  a  previous  pharmacopoeia,  he  must  specify  on 
his  prescription,  "U.S. P.  1880,"  "U.S. P.  1890,"  etc. 

Because  it  recognizes  so  many  seemingly  needless  drugs  and 
preparations,  the  Pharmacopoeia  has  been  much  criticized.  But 
it  is  to  be  borne  in  mind  that  the  Pharmacopoeia  does  not  con- 
sider primarily  the  usefulness  of  an  article,  but  merely  attempts 
to  standardize  those  drugs  and  preparations  which  are  in  ex- 
tensive use  by  physicians  in  any  part  of  the  country.  It  must 
also  standardize  all  substances  used  in  making  preparations, 
whether  or  not  of  medicinal  value. 

The  National  Formulary  is  a  book  issued  by  the  American 


DOSAGE  47 

Pharmaceutical  Association,  with  the  idea  of  standardizing  some 
non-pharmacopeial  preparations  that  are  in  common  use.  In  a 
prescription  the  letters  "N.  F."  following  the  name  of  a  prepara- 
tion (e.  g.,  lotio  plumbi  et  opii,  N.  F.)  call  for  the  dispensing  of  a 
preparation  made  according  to  the  formula  of  this  book. 

A  dispensatory  is  a  commentary  on  drugs,  a  general  reference 
work  on  the  botany,  pharmacognosy,  chemistry,  pharmacy, 
and  therapeutics  of  drugs.  It  is  an  extensive  work  and  is  not 
official.  The  United  States,  the  National,  and  King's  Dispensa- 
tories are  the  best  known  in  this  country,  and  Hager's  Praxis 
in  Germany.  They  give  a  vast  amount  of  information,  and  are 
encyclopedic  in  character,  scarcely  a  known  drug  escaping  some 
recognition. 

DOSAGE 

When  we  say  the  dose  of  a  drug,  we  mean  the  therapeutic  dose 
for  an  adult,  i.  e.,  the  amount  ordinarily  required  to  produce  a 
medicinal  effect.  The  Pharmacopoeia  gives  the  average  thera- 
peutic dose,  and  for  convenience  this  is  the  dose  to  learn,  in  most 
instances. 

The  minimum  dose  is  the  smallest  capable  of  producing  a 
medicinal  effect — not  quite  so  small,  however,  as  two  drops  of 
the  ninth  dilution  of  the  homeopaths,  which  Oliver  Wendell 
Holmes  estimated  to  be  of  the  strength  of  one  drop  in  ten  billion 
gallons.  A  maximum  dose  is  the  greatest  dose  that  can  be  ad- 
ministered without  probability  of  poisonous  effects.  A  toxic 
dose  is  a  poisonous  dose. 

Remedies  are  administered  either  in  single  doses  or  in  repeated 
doses.  A  single  dose  of  a  medicine  may  be  given  all  at  once,  as 
two  compound  cathartic  pills  or  an  ounce  of  whisky ;  or  in  divided 
doses,  as  when  one  grain  of  calomel  is  given  in  one-quarter  grain 
tablets,  one  every  half-hour  for  four  doses. 

Repeated  doses  may  be  intended  to  have  an  effect  just  at  the 
time  of  administration,  as  a  bitter  before  each  meal  to  improve 
the  appetite;  or  to  have  a  continuous  effect,  as  digitalis  for  a 
weakened  heart.  To  produce  a  continuous  effect,  remedies  are 
usually  given  three  or  four  times  a  day,  and,  as  a  rule,  it  is  too 
great  trouble  for  patients  to  take  medicine  more  often  than  this. 
Even  very  sick  patients  should  not  be  disturbed  by  too  frequent 
medication. 

Sometimes  a  powerful  drug  given  for  continuous  effect  is 
administered  in  too  large  amounts  for  ready  excretion,  so  that  it 
accumulates  in  the  system  until  poisonous  symptoms  appear. 
Such  a  drug  is  known  as  a  cumulative  poison.     The  ill  effects  are 


48  PHARMACOLOGY  AND  THERAPEUTICS 

dependent  upon  the  failure  of  elimination  to  keep  pace  with  the 
ingestion  of  the  drug.  The  most  common  drugs  to  give  cumula- 
tive effects  are  digitalis,  arsenic,  mercury,  and  lead.  Lead  and 
arsenic,  indeed,  are  so  slowly  excreted  that  they  may  accumulate 
in  the  system  even  when  taken  only  in  the  minutest  quantities 
at  a  time,  as  from  drinking-water  that  has  lain  in  leaden  pipes, 
or  breathing  the  air  of  a  room  with  an  arsenic  color  in  the  wall- 
paper. 

The  phrase  "pushing  a  drug  to  its  physiologic  limit"  is  some- 
times employed  when  a  remedy  is  given  in  gradually  increasing 
doses  until  toxic  symptoms  begin  to  appear. 

FACTORS  WHICH  MODIFY  THE  DOSE 

It  must  be  apparent  that  the  ordinary  average  adult  dose  is 
not  the  dose  for  every  one  under  all  circumstances.  Some  of 
the  factors  modifying  the  dose  are: 

i.  Body  Weight. — In  pharmacologic  experimentation  it  is 
customary  to  estimate  the  dosage  in  proportion  to  the  weight  of 
the  animal.  Within  certain  limits  this  should  be  a  good  method 
with  humans,  and  it  is  the  basis  of  Clark's  rule,  which  assumes 
that  the  average  weight  of  an  adult  is  150  pounds.     The  rule  is — 

wcisrht 

Adult  dose  X  -  — —  •     But  a  patient  in  bed  cannot  be  weighed, 

and  it  takes  an  expert  to  guess  such  a  one's  weight  correctly; 
and  a  man  with  dropsy  or  an  adipose  patient  would  have  some 
extraneous  weight  to  be  allowed  for.  So,  as  a  matter  of  fact, 
either  on  account  of  our  highly  organized  nervous  systems  or 
on  account  of  our  ways  of  eating  and  drinking  and  working,  or 
for  other  reasons,  the  rule  of  weight  does  not  seem  suitable  for 
practical  use. 

2.  The  Age. — It  is  evident  that  the  dose  for  an  adult  is  not 
the  same  as  that  for  a  child.  Yet  to  establish  a  working  rule  is 
not  easy,  for  not  only  is  there  no  regular  increase  in  a  child's 
weight  according  to  age,  but  there  is  also  unequal  development 
of  the  different  systems  of  the  body.  The  weight  rule  would  be 
the  best  but  for  its  difficulty  of  adoption,  and  to  multiply  the 
adult  dose  by  a  simple  fraction  with  the  child's  age  as  numerator 
and  the  supposed  earliest  adult  age  as  denominator,  will  not  be 
correct.  It  will  not  do,  for  example,  to  take  an  arbitrary  age 
of  twenty  or  twenty-four  as  the  adult  age,  and  take  one-twentieth 
or  one-twenty-fourth  for  each  year  of  the  child's  age.  The  fol- 
lowing table  of  the  average  weights  at  the  different  ages,  taken 
from  Bowditch's  statistics  in  8008  children  in  Boston,  and  Paster's 
of  14,744  children  in  St.  Louis,  as  recorded  by  Holt,  shows  how 
absurd  it  is  to  estimate  the  dose  at  two  years  as  twice  that  at  one 


FACTORS   WHICH   MODIFY   THE   DOSE  49 

year,  etc.  The  figures  given  are  for  the  boys,  those  for  the  girls 
being  for  the  most  part  not  more  than  one  to  three  pounds 
different. 

Age  Weight 

Half  year 16.0  pounds 

One  year 21.0 

Two  years 27.0 

Three  years 32.0 

Four  years 36.0 

Five  years 41.2 

Six  years 44.4 

Seven  years 48.6 

Eight  years 53.5 

Nine  years 58.7 

Ten  years 64.6 

Eleven  years 70.6 

Twelve  years 76.7 

Thirteen  years 83.7 

Fourteen  years 94.0 

Fifteen  years 107.3 

Sixteen  years 1 19.1 

From  these  figures  a  fairly  accurate  age-weight  rule  would  be: 

'— —  X  adult  dose.      In   other    words,    in    writing    for    30 

doses  (4  ounces  with  1  dram  dose)  put  down  as  many  minims  or 
grains  as  the  age  +  3;  in  writing  for  15  doses  (2  ounces  with  1 
dram  dose)  put  down  half  as  many  minims  or  grains  as  the 
age  +  3.  In  the  metric  system  put  down  the  adult  dose  (age 
+  3)  X  3,  and  move  the  decimal  point  two  places  to  the  left. 
Two  other  rules  in  common  use  are  Young's  and  Cowling's: 

Young's  rule  is:   Adult  dose  X         ,  T 2 

^      ,.  ,.         AJ1..J  w  age  at  next  birthdav        v 

Cowlings  rule  is:   Adult  dose  X  -  — .      In  pre- 

scribing  by  this  rule,  all  that  is  necessary  is  to  write  for  24 
doses  and  set  down  for  each  ingredient  the  adult  dose  multiplied 
by  the  age  at  next  birthday. 

Fried?  s  rule  for  infants  under  one  year  is  :  Adult  dose  X 

age  in  months 
150 

In  some  cases  these  rules  do  not  apply,  e.  g.,  children  react 
strongly  to  opium  and  other  narcotics,  while,  on  the  contrary, 
the  child's  dose  of  a  cathartic  or  belladonna  or  arsenic  approaches 
that  of  an  adult.  We  have  seen  the  same  amount  of  belladonna 
given  to  a  father  and  to  his  son  six  years  of  age  with  equal  effect ; 
and  a  child  of  three  years  not  one  whit  more  affected  by  a  grain 
of  calomel  than  was  her  mother  by  half  the  dose.  On  the  other 
hand,  we  have  seen  a  child  of  one  year  "  doped  "  by  one-twentieth 
of  a  grain  of  powdered  opium. 

In  old  age  the  dose  must  be,  as  a  rule,  somewhat  less  than  in 
4 


50  PHARMACOLOGY  AND   THERAPEUTICS 

the  prime  of  life;    and  especially  must  skin  irritants,  irritant 
cathartics,  narcotics,  and  depressant  drugs  be  used  with  caution. 

3.  Sex. — Women  usually  require  smaller  doses  than  men, 
not  only  because  of  their  average  smaller  stature  and  quieter 
life,  but  also  because  of  their  greater  susceptibility  to  any  in- 
fluences. During  menstruation  and  pregnancy  irritant  ca- 
thartics, and  during  lactation  saline  cathartics,  are  to  be  avoided 
or  used  with  caution. 

4.  Temperament,  Race,  Occupation. — The  patient  of  highly 
neurotic  temperament  is  more  susceptible  than  the  phlegmatic 
person.  Such  difference  may  be  racial,  the  excitable  Italian, 
for  example,  being  more  easily  affected  than  the  stolid  German; 
or  it  may  have  to  do  with  activity  and  occupation,  the  athlete 
or  the  man  who  works  all  day  out-of-doors  and  is  inured  to  hard- 
ship being  less  readily  affected  than  the  man  of  sedentary  habits, 
the  merchant,  student,  or  artist. 

5.  Previous  Habits  (Toleration). — The  morphine  habitue 
can  take  with  impunity  a  dose  of  morphine  large  enough  to  poison 
one  not  habituated,  and  will  obtain  no  effect  from  the  ordinary 
dose.  An  old  toper  with  cirrhosis  of  the  liver  will  fail  to  get  a 
medicinal  effect  from  the  usual  dose  of  a  tablespoonful  of  whisky. 

6.  Idiosyncrasy  and  Susceptibility. — Idiosyncrasy  is  that  con- 
dition in  which  a  patient  develops  special  and  unusual  effects 
from  a  remedy  or  food.  Some  people  develop  a  rash  after  eating 
strawberries,  others  after  eating  lobster,  fish,  or  buckwheat. 
Sometimes  all  the  members  of  a  family  show  such  an  idiosyncrasy 
to  some  special  article  of  food,  and  it  is  manifest  in  successive 
generations.  The  same  is  true  of  drugs.  A  minute  amount  of 
cocaine  dropped  in  the  eye  or  applied  to  the  nasal  mucous  mem- 
brane may  cause  dangerous  symptoms  in  one  patient,  though 
cocaine  is  used  in  the  eyes  and  noses  of  thousands  of  other  pa- 
tients without  any  untoward  symptoms  at  all ;  or  a  dose  of  anti- 
pyrine  may  be  followed  by  a  marked  rash,  which  recurs  each  time 
the  drug  is  taken.  These  are  unusual  and  unexpected  effects, 
and  depend  not  so  much  on  the  size  of  the  dose  as  upon  a  specific 
and  unusual  hypersusceptibility  of  the  patient  toward  the  drug. 

An  ordinary  increase  of  susceptibility  means  lowered  resistance 
— a  condition  in  which  the  usual  or  expected  effects  are  produced 
by  less  than  the  usual  amounts.  For  example,  two  or  three 
grains  of  quinine  sulphate  produce  in  some  people  the  ringing 
in  the  ears,  deafness,  and  headache  that  in  most  persons  do  not 
come  from  less  than  10  or  20  grains.  Diminished  susceptibility 
means  heightened  resistance,  the  patient  showing  the  usual 
effects,  but  only  after  larger  doses  than  usual.  For  example, 
some  persons  can  take  two  or  three  cups  of  coffee  and  then  sleep 


FACTORS   WHICH   MODIFY    THE   DOSE  5 1 

soundly,  though  this  is  enough  to  keep  the  average  person  wide 
awake  for  hours. 

7.  The  Nature  of  the  Disease. — In  great  pain,  as  in  peri- 
tonitis, morphine  may  be  borne  in  doses  that  would  ordinarily 
be  poisonous.  On  the  contrary,  in  cyanosis  or  conditions  with 
bad  breathing,  morphine  should  be  used  with  caution  because  of 
its  tendency  to  depress  the  respiration.  In  malaria,  quinine 
can  be  borne  in  larger  doses  than  when  it  is  used  for  other  pur- 
poses. 

Again,  in  Bright 's  disease  or  other  conditions  involving  the 
eliminating  organs  drugs  may  more  readily  accumulate  in  the 
system  and  cause  cumulative  poisoning,  and  in  functional  or 
organic  disturbance  of  the  liver  certain  substances,  like  phenol 
or  morphine,  may  have  a  more  pronounced  poisonous  effect  than 
otherwise. 

8.  The  Object  of  the  Medication. — Quinine  as  a  bitter  appe- 
tizer may  be  given  in  doses  of  one  or  two  grains,  while  quinine 
for  malaria  is  given  in  a  single  large  dose  of  15  or  20  grains,  fol- 
lowed by  5  grains  three  times  a  day  for  a  month.  In  a  cough 
mixture  for  a  child  syrup  of  ipecac  is  given  in  dose  of  2  to  5 
minims,  but  in  croup,  where  an  emetic  effect  is  desired,  a  whole 
teaspoonful  is  administered. 

It  is  to  be  noted  that  preparations  for  local  action  are  active 
according  to  their  percentage  strength  rather  than  according  to 
the  actual  amount  of  drug  employed. 

9.  The  Form  of  the  Remedy. — As  a  rule,  this  makes  but  little 
difference;  yet,  other  things  being  equal,  liquids  are  more  rapidly 
active  than  solids,  and  alcoholic  liquids  more  than  aqueous. 
Active  principles  are  more  rapid  than  crude  drugs,  powders 
and  dry-filled  capsules  than  pills,  fresh-made  pills  than  coated 
pills.  Some  cathartic  drugs,  like  aloes  and  cascara,  are  more 
effective  cathartics  than  their  active  principles.  This  is  because 
of  the  extractive  matter  present,  which  retards  absorption  and 
keeps  the  active  principles  in  the  alimentary  tract  until  they  reach 
the  colon. 

10.  The  Channel  of  Administration. — It  has  usually  been 
taught  that  the  hypodermatic  dose  should  be  half,  and  the  dose  by 
rectum  twice,  that  by  mouth.  In  a  number  of  instances,  how- 
ever, it  has  been  demonstrated  that  drugs  are  as  quickly  absorbed 
from  the  rectum  as  from  the  stomach,  or  even  more  quickly;  and 
also  that,  in  ordinary  circumstances,  most  drugs  are  absorbed 
from  the  stomach  or  duodenum  with  sufficient  rapidity  to  give  the 
full  effect  of  the  drug  in  a  short  time ;  and  since  rectal  and  hypo- 
dermatic medication  are  resorted  to  only  under  special  circum- 
stances, their  dose  is  the  same  as  that  by  mouth.     In  rectal 


52  PHARMACOLOGY  AND  THERAPEUTICS 

medication  the  strength  of  the  preparation  rather  than  the  total 
dose  is  usually  desired,  for  the  rectum  is  seldom  resorted  to  for 
any  but  local  medication.  In  intravenous  medication  the  dose  is 
a  special  one  for  the  few  drugs  that  may  be  so  administered,  and 
is  usually  comparatively  small. 

ii.  The  Time  of  Administration. — After  meals  the  dose  is 
diluted  and  absorption  delayed  by  the  admixture  with  the  stom- 
ach-contents; so  if  a  rapid  effect  is  desired,  a  larger  dose  must  be 
given.  On  the  contrary,  the  empty  stomach  allows  immediate 
local  action  and  more  ready  absorption,  as  commonly  observed 
in  the  greater  activity  of  alcoholic  drinks  taken  before  meals. 

12.  The  Frequency  of  Administration. — It  goes  without 
saying  that  the  dose  of  a  powerful  drug  is  less  if  it  is  administered 
every  hour  or  two  than  if  given  three  times  a  day. 

ADMINISTRATION 

By  administration  is  meant  the  manner  in  which  the  remedy 
is  to  be  used.  Remedies  are  administered  to  obtain  either  a  direct 
local  action,  a  systemic  action,  or  a  remote  local  action. 

The  direct  local  action  is  the  action  at  the  place  at  which  the 
drug  is  applied,  as  on  the  skin,  or  in  nose,  throat,  stomach, 
urethra,  etc.  To  obtain  direct  local  action,  ointments,  lini- 
ments, plasters,  etc.,  are  employed.  Local  remedies  may  or  may 
not  require  to  be  absorbed.  Talcum  powder  applied  to  a  chafed 
skin,  or  bismuth  subnitrate  given  for  irritated  stomach  or  bowels, 
acts  by  coating  the  skin  or  mucous  membrane  and  is  not  absorbed ; 
while  cocaine,  to  produce  a  local  anesthetic  effect,  must  be  ab- 
sorbed to  get  at  the  nerve-endings  or  nerves  beneath  the  epi- 
dermis. 

The  systemic  action  is  the  action  of  the  drug  after  its  absorp- 
tion into  the  circulation,  as  that  of  strychnine  on  the  spinal  cord, 
or  pilocarpine  on  the  nerve-endings  in  the  sweat-glands. 

The  remote  local  action  is  the  effect  of  the  drug  as  it  is  being 
excreted,  e.  g.,  the  irritation  of  the  bowels  by  mercuric  chloride 
as  it  is  passed  out  by  the  colon  glands,  or  the  antiseptic  action  of 
urotropine  as  it  is  eliminated  in  the  urine.  To  obtain  either  a 
systemic  action  or  a  remote  local  action  the  drug  must  be  ab- 
sorbed;  that  is,  must  become  a  constituent  of  the  body  fluids. 

THE  WAYS  IN  WHICH  DRUGS  MAY  BE  ADMINISTERED   FOR 
SYSTEMIC  AND  REMOTE  LOCAL  EFFECT 

A.  By  mouth,  the  usual  way,  the  drug  being  swallowed  and 
absorbed  into  the  system  from  the  alimentary  tract. 

B.  Subcutaneously  (hypodermatically),  the  drug  being  intro- 


ADMINISTRATION  53 

duced  beneath  the  skin  by  means  of  a  special  hollow  needle  and 
a  syringe.  To  be  used  thus,  a  preparation  must  be  in  liquid  form, 
and,  as  a  rule,  in  complete  solution;  though  in  some  instances, 
as  in  the  use  of  insoluble  mercury  salts,  the  drug  may  be  in  the 
form  of  a  fine  powder  held  in  suspension  in  oil.  A  substance  for 
hypodermatic  use  must  be  capable  of  complete  absorption,  or  it 
will  act  as  a  foreign  body;  and  must  be  in  small  quantity,  be- 
cause large  amounts  will  produce  too  great  separation  of  the 
tissues.  Irritant  drugs  are  only  occasionally  given  hypoder- 
matically,  both  because  they  are  painful  and  because  they  may 
produce  necrosis  of  cells  with  abscess  formation.  Such  ab- 
scesses are  sterile,  however,  as  they  are  not  caused  by  pathogenic 
bacteria. 

For  convenience,  many  drugs  are  put  up  in  the  form  of  tab- 
lets called  hypodermic  tablets.  They  are  made  of  the  drug  and 
finely  powdered  cane-sugar  mixed  together,  moistened  with 
alcohol,  and  forced  into  molds.  When  dry,  they  can  be  handled 
without  disintegration,  but  are  readily  soluble.  (Tablets  made 
by  compression  do  not  dissolve  so  easily.)  Hypodermic  tablets 
of  salts  of  morphine,  atropine,  strychnine,  etc.,  can  be  carried  in 
a  pocket-case;  when  wanted,  they  may  be  placed  in  the  syringe 
and  dissolved  there  in  sterile  water  drawn  up  to  make  the  solu- 
tion, or  may  be  made  into  a  solution  with  a  few  drops  of  water  in 
a  spoon.  For  sterilization  the  water  may  be  heated  in  a  spoon 
over  a  spirit-lamp  or  a  gas-burner.  Drugs  dissolved  in  normal 
salt  solution  (0.9  per  cent.  NaCl)  tend  to  be  less  irritant  to  the 
tissues  and  more  readily  absorbed  than  those  dissolved  in  plain 
water,  but  when  the  total  amount  of  the  solution  is  very  small, 
tap-water  will  do. 

To  give  a  hypodermatic  injection,  the  dose  is  placed  in  the 
hypodermic  syringe  (many  liquids  cannot  readily  be  drawn  up 
through  the  syringe  needle),  the  sterilized  needle  (it  may  be 
sterilized  in  a  test-tube  or  spoon)  is  screwed  on,  and  the  syringe 
is  turned  needle  upward  so  that  any  bubbles  of  air  may  be  driven 
out  by  pressure  on  the  piston. 

There  are  two  methods  of  injection  for  systemic  effect,  the 
subcutaneous  and  the  intramuscular.  In  the  subcutaneous 
method  the  properly  cleansed  skin,  usually  of  an  arm  or  a  leg, 
is  pinched  up  between  the  thumb  and  finger  of  one  hand,  while 
the  needle  is  quickly  plunged  in  a  slanting  direction  through  the 
skin  into  the  subcutaneous  tissue.  In  the  intramuscular  method 
the  needle  is  plunged  straight  through  the  skin  and  subcutaneous 
tissue  into  the  underlying  muscle,  usually  in  the  back,  buttocks, 
or  chest,  though  sometimes  in  the  limbs.  This  method  favors 
ready  absorption.     By  either  method,  a  sharp  needle  and  quick 


54  PHARMACOLOGY  AND  THERAPEUTICS 

puncture  give  almost  no  pain.  The  fluid  is  slowly  injected,  the 
needle  is  quickly  withdrawn,  the  point  of  the  puncture  is  covered 
to  prevent  the  fluid  from  running  out,  and  the  spot  is  gently 
massaged  to  promote  diffusion  of  the  liquid  into  the  tissues. 
The  hypodermatic  needle  may  be  cleansed  by  first  forcing  water 
through  it,  and  then  allowing  a  few  drops  of  alcohol  to  descend 
through  it  by  capillarity.  A  fine  wire  drawn  through  the  lumen 
keeps  it  permeable.  (In  the  introduction  of  cocaine  and  similar 
drugs  for  local  anesthesia  where  a  local  action  only  is  desired,  the 
needle  is  inserted  just  beneath  the  epidermis  and  gives  a  superficial 
subcutaneous  injection,  or  an  intracutaneous  injection.  This 
method  is  not  used  when  a  systemic  effect  is  desired.) 

There  are  certain  advantages  and  disadvantages  in  hypo- 
dermatic medication. 
The  advantages  are: 
i.  Certainty  of  action — all  the  drugs  get  into  the  tissues; 

therefore  the  dose  is  more  definite. 
2.  Rapidity  of  action — because  the  drug  in  most  instances 
quickly  reaches  the  circulation  by  means  of  the  capil- 
laries or  lymphatics, 
j.  Availability — when  administration  by  mouth  is  not  feasible, 
as  when  (i)  the  patient  cannot  swallow,  as  in  uncon- 
sciousness;   or  (2)  will  not  swallow,  as  in  drunkenness 
or  delirium — or  when  drugs  are  taken  with  suicidal 
intent;   or  (3)  the  alimentary  tract  is  in  a  state  of  in- 
tolerance   and    non-absorption,    as    in    uncontrollable 
vomiting  or  diarrhea. 
The  disadvantages  are  seldom  encountered.     They  are: 

1.  The  chance  of  abscess  formation,  either  a  sterile  abscess 

from  an  irritant  drug,  or  an  infective  abscess  from  un- 
sterile  solution,  needle,  or  skin. 

2.  The  chance  of  injecting  the  drug  into  a  vein.     This  would 

plunge  the  whole  dose  into  the  circulation  at  once,  per- 
haps with  disastrous  results.  To  avoid  this  the  syringe 
may  be  unscrewed  from  the  needle ;  if  blood  oozes  from 
the  needle,  it  is  withdrawn  and  inserted  elsewhere. 

3.  The  chance  of  injecting  the  drug  into  a  nerve,  with  result- 

ing great  pain. 

Hypodermatic  medication  has  a  very  restricted  employment, 
because  only  those  drugs  whose  dose  in  solution  is  of  small  bulk 
are  available  for  this  method  of  administration. 

C.  By  hypodermatodysis,  in  which  a  large  quantity  of  saline 
liquid  (50  to  500  c.c.)  is  injected  into  the  loose  tissues  about  the 
breasts  or  abdomen,  or  into  the  back  below  the  scapula,  or  into 
the  buttocks.     This  amount  of  liquid  causes  great  separation  of 


THE    TIME    OF    ADMINISTRATION  55 

the  tissues;  and  if  it  is  not  isotonic,  or  nearly  so,  with  the  blood, 
or  if  it  interferes  by  pressure  with  the  circulation  of  the  part,  it 
may  result  in  gangrene  or  abscess.  The  writer  has  seen  extensive 
gangrene  follow  the  injection  of  200  c.c.  of  2  per  cent,  solution 
of  sodium  carbonate  in  a  diabetic. 

D.  By  Rectum. — Drugs  may  be  placed  in  the  rectum  by  means 
of  an  enema,  i.  e.,  a  rectal  injection,  or  in  the  form  of  a  supposi- 
tory or  ointment.  The  uncertainty  of  absorption  and  the  chance 
that  the  drug  will  be  expelled  limit  the  usefulness  of  this  channel 
and  largely  restrict  it  to  drugs  for  local  effect  only.  Proctoclysis 
is  a  rectal  irrigation  or  injection  intended  for  both  local  and 
systemic  effect.  It  is  usually  made  with  saline  or  medicated 
saline  fluids. 

E.  By  the  skin,  by  inunction,  in  which  an  oily  or  fatty  pre- 
paration is  rubbed  upon  the  skin  and  left  to  be  absorbed.  On 
account  of  uncertainty  of  absorption  the  dose  may  vary  within 
wide  limits.  Mercurial  ointment  is  so  used  in  the  treatment  of 
syphilis,  and  cod-liver  oil  and  cocoa-butter  in  the  treatment  of 
malnutrition. 

F.  By  the  Veins,  Intravenous  Medication. — Drugs  adminis- 
tered by  a  vein  act  with  great  promptness,  the  whole  dose  passing 
at  once  into  the  circulation.  Intravenous  medication  may  be 
by  injection  or  by  infusion.  In  intravenous  injection  the  drug, 
diluted  with  a  small  quantity  of  normal  salt  solution,  is  injected 
from  a  syringe,  the  needle  being  plunged  through  the  wall  of  the 
vein^  in  a  slanting  direction  and  toward  the  heart.  When  the 
needle  is  withdrawn,  the  valve-like  opening  thus  made  usually 
closes  of  itself,  though  sometimes  there  is  a  moderate  extra- 
vasation of  blood  into  the  tissues.  In  intravenous  infusion  sl 
large  quantity  of  warm  normal  saline  solution  (500  to  1500  c.c), 
or  some  isotonic  liquid,  with  or  without  the  addition  of  drugs, 
is  slowly  passed  into  the  vein  through  a  suitable  nozle.  This 
requires  tying  a  vein,  so  it  cannot  be  repeated  more  than  once  or 
twice,  and  is  employed  only  in  emergencies. 

G.  Through  the  lungs  by  inhalation — of  gas  for  absorption  into 
the  system,  as  in  the  use  of  chloroform  or  ether  as  a  general 
anesthetic.  (Inhalations  of  medicated  vapors  are  employed 
also  for  a  local  effect  on  the  respiratory  organs.) 

THE  TIME  OF  ADMINISTRATION 

This  is  of  some  importance,  e.  g.,  the  saline  cathartics  act 
most  rapidly  after  a  period  of  fasting,  so  are  usually  adminis- 
tered before  breakfast.  Irritant  drugs,  as  arsenic  or  iron  or 
digitalis,  are  best  given  after  meals,  when  they  become  well 
diluted  with  the  stomach-contents,  and  come  very  little  in  contact 


56  PHARMACOLOGY  AND   THERAPEUTICS 

with  the  stomach-wall  to  irritate  it.  Quinine  sulphate  is  given 
after  meals  not  only  because  it  is  irritant,  but  so  that  it  may  be 
dissolved  by  the  acid  gastric  juice;  otherwise  its  absorption  is 
retarded  or  may  not  take  place  at  all.  Sleep  producers  are  most 
effective  at  the  natural  time  of  sleeping,  and  when  the  surround- 
ings are  favorable  to  sleep;  they  may  have  no  effect  at  all  if  the 
patient  is  up  and  about.  Sodium  bicarbonate  given  on  an  empty 
stomach,  i.  e.,  before  a  meal,  is  absorbed  as  sodium  bicarbonate, 
and  furnishes  alkali  directly  to  the  blood;  but  if  it  is  given  during 
the  digestive  period,  it  neutralizes  the  hydrochloric  acid  of  the 
gastric  juice,  is  changed  to  sodium  chloride,  and  sets  free  carbon 
dioxide.     Appetizers  must  be  given  just  preceding  the  meal. 

SITES  AND  MODES  OF  ACTION  OF  DRUGS 

Drugs  may  act  as  such: 

i.  Independently  of  the  human  body,  as  antiseptics  on  micro- 
organisms in  disinfection. 

2.  In  or  about  the  human  body,  but  not  on  its  structures,  as  in 
the  destruction  of  a  tape-worm,  skin  parasites,  etc.,  or  as  in  the 
neutralization  of  a  hyperacid  gastric  juice  by  an  alkali. 

j.  On  the  structures  of  the  human  body.  Drugs  may  act  on 
the  tissues — (a)  Through  their  physical  or  mechanical  properties, 
as  when  cold  cream  is  applied  to  a  chapped  face  to  soften  the 
epithelium  and  prevent  its  drying;  or  when  bismuth  subnitrate, 
given  for  diarrhea,  coats  the  mucous  membrane  of  the  bowel 
and  soothes  and  protects  it.  Or  they  may  act  (b)  by  their 
chemic  affinity  for  one  or  other  constituent  of  protoplasm,  so 
that  either  the  functional  power  of  the  cell  or  the  actual  cell 
structure  is  changed.  Some  of  these  are  general  in  their  action, 
affecting  practically  all  forms  of  protoplasm  (though  not  all 
forms  to  a  like  degree),  and  when  the  action  of  these  drugs  is 
powerful,  they  are  known  as  general  protoplasm  poisons.  Such 
are  alcohol,  chloral  hydrate,  and  quinine.  Other  drugs  are 
selective,  exerting  their  influence  only  on  special  groups  of  cells 
and  having  no  effect  upon  the  vast  majority  of  body  structures. 
This  is  presumably  owing  to  a  chemic  affinity  for  some  com- 
ponent of  the  cell.  Such  drugs  are  strychnine,  which  has  a 
selective  affinity  for  certain  portions  of  the  central  nervous 
system,  and  pilocarpine,  which  has  an  affinity  for  secretory  nerve- 
endings. 

The  effect  of  drugs  on  cells  is  to  stimulate  them,  to  depress 
them,  or  to  change  and  destroy  them.  Stimulation  is  an  effect 
on  cells  by  which  their  power  or  their  readiness  to  functionate 
is  increased.     Depression  is  an  effect  on  cells  by  which  their 


SYNERGISTS   AND   ANTAGONISTS  57 

power  or  readiness  to  functionate  is  lessened.  Paralysis  is  the 
cessation  of  the  power  to  functionate. 

Irritation  implies  an  anatomic  rather  than  a  functional  effect, 
tending  toward  the  harmful.  It  has  to  do  with  actual  changes 
in  the  cell  structure.  In  its  mild  degrees  irritation  may  have  the 
effect  of  stimulation;  in  stronger  forms  irritation  may  overwhelm 
the  cells  and  have  the  effect  of  depression;  while  excessive  or 
continued  irritation  induces  inflammation  and  even  actual  death 
of  the  cells  involved.  As  an  example,  take  cantharides,  an  irritant 
to  the  kidney-cells;  from  small  doses  the  cells  are  made  to  func- 
tionate more  actively,  and  increased  urination  takes  place,  but 
from  toxic  amounts  the  irritation  results  in  inflammation,  so 
that  nephritis  sets  in,  with  destruction  of  cells,  impairment  of 
function,  and,  perhaps,  suppression  of  the  urine. 

By  exhaustion  from  overwork,  continued  stimulation  may  re- 
sult in  depression  or  even  complete  cessation  of  the  work  of  the 
cells,  but  this  is  a  functional  inactivity  from  fatigue,  and  a  period 
of  rest  and  nutrition  will  usually  restore  the  cells'  power. 

Often  a  drug  will  be  found  to  stimulate  one  structure  and 
depress  another,  as  atropine,  which  stimulates  the  vagus  center 
and  depresses  the  vagus  endings;  or  pilocarpine,  which  stimu- 
lates the  nerve-endings  in  the  sweat-glands  and  tends  to  depress 
heart  muscle. 

SYNERGISTS  AND  ANTAGONISTS 

As  might  be  surmised,  the  same  dose  of  a  drug  will  exert  its 
usual  form  of  activity  more  easily  if  given  with  other  drugs  of 
the  same  class;  and  sometimes  a  combination  of  two  similar 
drugs  will  gain  a  result  that  one  alone  will  not  give  in  any  dose. 
Drugs  which  help  each  other  in  this  way  are  known  as  synergists, 
or  mutual  helpers,  and  examples  are  bromides  and  chloral  hydrate 
for  sleep,  calomel  and  jalap  for  catharsis. 

On  the  contrary,  a  drug  may  lose  part  or  all  of  its  power 
because  of  some  agent  that  has  the  opposite  physiologic  effect. 
Such  opposing  agents  are  known  as  antagonists.  An  antagonist 
may  be  a  drug,  or  it  may  be  a  substance  formed  in  the  body,  as 
adrenaline  or  thyroid  extract  or  some  antitoxin.  The  antagonists 
may  act — (a)  on  the  same  structures — for  example,  bromides  pre- 
vent the  convulsions  of  strychnine,  both  acting  on  the  spinal 
cord;  caffeine  stimulates  the  psychic  and  motor  centers  of  the 
cerebrum,  while  alcohol  depresses  them;  pilocarpine  stimulates 
the  vagus  nerve-endings,  which  are  depressed  by  atropine;  (b) 
on  different  structures — for  instance,  digitalis  slows  the  heart  by 
stimulating  the  vagus  center,  while  atropine  prevents  this  effect 
by  depressing  the  vagus  nerve-endings;    adrenaline  stimulates 


58  PHARMACOLOGY  AND  THERAPEUTICS 

the  nerve-endings  in  arterial  muscle,  causing  contraction  of  the 
arteries,  and  this  effect  can  be  wholly  neutralized  by  nitrogly- 
cerin, which  depresses  the  arterial  muscle  itself. 

Incompatibility  should  not  be  confused  with  antagonism.  It 
is  a  pharmaceutic  term,  and  is  best  confined  to  prescriptions. 
Incompatibility  may  be  said  to  exist  between  two  substances 
when  their  admixture  in  a  prescription  results  in  chemic  or  physi- 
cal change  (other  than  mere  solution).  Examples  are  the  pre- 
cipitation when  strychnine  sulphate  in  solution  comes  in  contact 
with  tannic  acid,  or  when  lead  acetate  solution  is  mixed  with  a 
solution  of  alum.  Such  a  change  may  or  may  not  be  desired  in 
a  prescription;  hence  the  physician  should  know  what  changes 
may  take  place  in  substances  likely  to  be  prescribed  together. 
(See  Chapter  on  Prescriptions.) 


SCIENTIFIC  AND  EMPIRIC  THERAPEUTICS— ANIMAL 
EXPERIMENTATION 

Besides  the  constituents,  the  preparations,  and  the  pharma- 
cology of  a  drug,  we  are  to  learn  its  therapeutics,  and,  we  might 
ask,  how  have  our  drugs  come  to  have  their  present  uses  in 
medicine? 

From  the  employment  of  hepatica  for  liver  diseases  because 
its  leaf  suggested  the  liver,  to  the  employment  of  drugs  because 
of  known  actions  determined  by  animal  experimentation  and 
therapeutic  tests  is  a  far  cry,  yet  it  represents  only  a  few  years  of 
time,  and  indicates  the  rapid  strides  that  are  being  made  toward 
the  establishment  of  therapeutics  on  a  sound  scientific  basis. 
The  use  of  drugs  without  an  adequate  scientific  explanation  of 
their  efficiency  is  empiric.  For  instance,  colchicum  is  exten- 
sively employed  as  a  remedy  in  gout,  though  no  pharmacologic 
study  has  as  yet  indicated  how  or  why  colchicum  should  be  of 
benefit  in  this  disease.  We  give  it  in  gout  for  no  other  reason 
than  that  we  believe  that  it  has  worked  before;  in  other  words, 
we  use  it  empirically. 

As  a  matter  of  fact,  animal  experimentation  is  rapidly  rele- 
gating empiric  remedies  to  the  realm  of  disuse;  and  many 
beliefs  in  the  efficacy  of  remedies  have  yielded  to  the  adverse 
proof  of  experiment.  Indeed,  very  few  of  the  advances  of  the 
last  half-century  could  have  been  made  but  for  the  use  of  animals 
in  the  study  of  the  action  of  drugs,  for  detailed  experiments  on 
human  beings  are  obviously  out  of  the  question.  Anrep,  working 
with  animals,  discovered  the  effects  of  cocaine  as  a  local  anes- 
thetic; antipyrine,  phenacetin,  and  a  number  of  so-called  coal- 
tar  products  owe  their  use  to  an  observation  by  Filehne  that 


SCIENTIFIC   AND    EMPIRIC    THERAPEUTICS  59 

antipyrine  reduced  the  temperature  of  animals  put  into  fever 
by  experimental  infection.  The  actions  of  nitrites,  of  thyroid 
extract,  of  saline  infusions,  of  diphtheria  antitoxin,  etc.,  are  all 
known  as  the  result  of  animal  experiments. 

In  this  connection  it  is  an  interesting  fact  that  many  of  the 
most  important  discoveries  have  resulted  from  purely  academic 
studies,  studies  made  without  thought  of  finding  substances 
useful  to  man.  For  example,  the  hypnotic  power  of  chloral 
hydrate  was  the  outcome  of  Liebreich's  attempt  to  solve  the 
purely  physiologic  question  as  to  whether  or  not  a  substance 
is  broken  up  into  its  constituent  parts  before  it  is  oxidized.  The 
sleep-producing  power  of  sulfonal  was  discovered  in  a  study  of 
the  effects  of  organic  sulphur  compounds  on  metabolism.  The 
power  of  adrenaline  to  constrict  the  arteries  and  raise  blood- 
pressure  was  first  noted  in  animal  experimentation  conducted 
with  no  thought  of  therapeutic  possibilities.  And  the  recent 
wonderful  additions  to  our  knowledge  of  the  irregularities  of  the 
heart  may  be  attributed  largely  to  some  incidental  observations 
of  Cushny  and  others  while  performing  laboratory  experiments 
without  a  thought  of  their  ultimate  usefulness  to  man. 

These  illustrations  suggest  what  important  discoveries  might 
be  lost  to  us  if  animal  experimentation  were  to  be  undertaken  only 
with  the  definite  object  of  lessening  human  ills.  If  to  these 
therapeutic  agents  which  we  owe  to  experiments  on  animals 
we  add  the  knowledge  of  the  body  processes,  of  disease  condi- 
tions, of  the  transmission  of  disease,  and  of  the  development  of 
immunity,  it  makes  enormous  the  sum  of  the  obligations  of 
medical  science  and  human  sufferers  to  animal  experimentation, 
commonly  known  as  vivisection.  Yet  in  recent  years  a  goodly 
number  of  people  who  profess  to  believe  that  no  animal  should 
be  sacrificed  for  the  good  of  human  beings,  have  made  the  most 
strenuous  efforts  to  bring  about  legislation  restricting  vivisec- 
tion. Their  harrowing  descriptions  of  experiments,  their  grossly 
exaggerated  statements  as  to  the  failure  of  experimenters  to 
protect  the  animals  from  pain,  and  as  to  the  brutality  of  the 
experimenters  themselves,  have,  unfortunately,  led  many  people 
of  prominence  to  give  them  support,  and  have  made  it  incumbent 
upon  all  physicians  who  are  in  a  position  to  know  the  facts  to 
combat  in  every  way  this  retrograde  movement.  The  medical 
man,  of  all  persons,  is  in  the  best  position  to  realize  how,  in  the 
absence  of  vivisection  to  establish  exact  data,  every  attempt  to 
treat  the  sick,  especially  by  the  new  medical  graduate,  " would 
be  nothing  less  than  an  experiment  in  human  vivisection,  which 
animal  experimentation  now  renders  needless." 


60  PHARMACOLOGY   AND    THERAPEUTICS 


THE  SCOPE  OF  TREATMENT 

Treatment  may  be  described  as  either  specific,  symptomatic, 
or  expectant. 

Specific  treatment  is  that  in  which  a  remedy  directly  attacks 
the  causative  factors  of  the  disease.  In  the  diseases  for  which 
such  specific  remedies  are  known  the  diagnosis  at  once  deter- 
mines the  remedy,  e.  g.,  in  diphtheria  the  remedy  is  diphtheria 
antitoxin;  in  acute  articular  rheumatism,  salicylic  acid;  in 
malaria,  quinine;  in  syphilis,  salvarsan  and  mercury.  In  each 
of  these  diseases  there  is  no  question  as  to  the  remedy,  for  it 
is  specific. 

But  for  almost  all  the  diseases  which  a  physician  is  called 
upon  to  treat,  such  as  tonsillitis,  typhoid  fever,  cirrhosis  of  the 
liver,  etc.,  there  is  no  specific  remedy,  so  that  he  is  forced  to  con- 
tent himself  with  attempts  to  combat  the  various  harmful  symp- 
toms and  their  effects  as  they  appear,  i.  e.,  he  employs  symp- 
tomatic treatment.  Thus  in  typhoid  fever,  if  there  is  constipation, 
a  drug  with  a  laxative  action  is  given;  if  diarrhea,  a  constipating 
drug;  if  there  is  a  weak  heart,  a  cardiac  stimulant  may  be  ad- 
ministered, and  if  the  heart  is  in  good  condition  it  needs  no  drug 
at  all.  Hence  in  many  cases  of  typhoid  fever  no  remedy  is  re- 
quired for  days  at  a  time,  for  none  of  the  manifestations  of  the 
disease  are  pronounced  enough  to  demand  special  antagonizing, 
and  we  know  of  no  remedy  that  will  cure  the  disease  itself. 
Again,  in  such  a  disease  as  cirrhosis  of  the  liver,  where  certain 
tissues  are  destroyed  and  cannot  by  any  known  means  be  re- 
stored, treatment  is  directed,  essentially,  to  combating  such 
symptoms  as  result  from  the  impairment  of  the  diseased  organ, 
and  perhaps,  also,  to  promoting  the  functional  power  of  such 
portions  of  the  organ  as  are  still  good.  These  are  conditions  for 
symptomatic  treatment.  In  fact,  almost  all  internal  treatment 
is  symptomatic  treatment,  and  it  is  because  of  this  fact  that  a 
knowledge  of  the  power  of  remedies  to  modify  the  structure  or 
functions  of  the  various  organs  of  the  body  is  so  important  to  the 
physician. 

Expectant  treatment  is  a  term  applied  to  the  administration 
of  mild  and  harmless  remedies  while  the  development  of  symp- 
toms is  awaited.  For  example,  if  one  sees  a  child  with  fever 
but  cannot  diagnosticate  the  disease  at  the  first  visit,  one  may 
prescribe  some  of  the  official  solution  of  ammonium  acetate, 
which  satisfies  the  patient  and  the  family,  tends  to  do  good,  does 
no  harm,  and  does  not  interfere  with  the  later  diagnosis  of  the 
disease.  Expectant  treatment  should  not  be  employed  if  its  neces- 
sity can  be  avoided.     A  remedy  employed  in  expectant  treatment 


HOW   MUCH   SHALL   WE   LEARN  ABOUT  DRUGS?  6l 

is  known  as  a  placebo  ("I  placate  or  please"),  and  in  the  selec- 
tion of  a  placebo  it  is  well  to  choose  one  with  some  fitness  to  the 
case  in  hand,  as  the  spirit  of  mindererus  in  fever,  so  that  the 
tendency  will  be  good  even  though  its  power  is  slight.  In  neu- 
rotic conditions  a  placebo  is  often  administered  for  its  psychic 
effect. 


HOW  MUCH  SHALL  WE  LEARN  ABOUT  DRUGS? 

The  subject  of  the  materia  medica  is  an  extensive  one,  and  the 
text-books  contain  many  things  that  the  physician  does  not  need 
to  know.  He  need  not  learn  the  pharmacopeial  definition,  where 
and  how  a  drug  grows,  the  method  of  its  collection,  its  physical 
and  microscopic  characters,  its  preparation  for  the  market,  its 
adulterants,  the  process  of  manufacture  of  chemic  drugs,  the 
shapes  of  crystals,  melting-points,  etc.  Such  data  are  for  the 
pharmacist,  the  chemist,  and  the  pharmacognosist,  the  men 
upon  whom  the  physician  must  depend  for  his  proper  supply  of 
good  drugs. 

But  as  physicians  we  need  to  know  the  following: 

i.  The  English  and  Latin  names  of  drugs  and  their  prepara- 
tions. In  prescriptions  we  use  the  Latin  names  only,  but  in  the 
literature  find  both  the  English  and  the  Latin,  so  we  must  know 
both.  We  learn,  therefore,  that  ficus  is  fig,  and  zingiber  is 
ginger,  and  rhamnus  purshiana  is  cascara,  and  mistura  cretce  is 
chalk  mixture.  (See  also  Use  of  Latin  in  chapters  on  Pre- 
scription-writing.) 

2.  The  Active  Constituents  of  Organic  Drugs. — Of  particular 
importance  are  those  active  constituents  which  are  isolated  from 
the  drug  and  used  by  themselves  in  medicine,  as  morphine, 
strychnine,  salicin,  menthol,  etc.,  or  those  which  make  unde- 
sirable incompatibles,  as  tannic  acid. 

j.  The  solubilities  and  incompatibilities  of  chemic  drugs  and 
of  active  constituents,  where  these  become  of  importance  from  a 
prescription  or  utility  point  of  view. 

4.  Preparations,  with  their  Strengths  and  Doses. — These  are 
the  official  preparations,  and  such  unofficial  ones  as  are  in  com- 
mon use.  To  know  at  least  some  of  them  is  essential  to  the 
writing  of  prescriptions,  for  not  only  are  the  official  preparations 
the  ones  that  are  made  of  uniform  strength  throughout  the  United 
States,  but  they  are  the  forms  in  which  a  remedy  can  be  con- 
veniently obtained. 

The  average  dose  is  given  in  the  Pharmacopoeia,  and  this, 
in  most  instances,  is  the  dose  to  learn;  and  since  what  is  desired 
for  the  patient  is  a  therapeutic  dose  of  the  drug  itself,  the  dose  of 


62  PHARMACOLOGY  AND  THERAPEUTICS 

the  preparation  should  be  such  an  amount  as  will  represent  the 
desired  dose  of  the  drug.  The  learning  of  doses  is  greatly  facili- 
tated by  the  pharmacopeial  custom  of  having  one  strength  for 
all  the  more  powerful  preparations  of  a  given  class.  For  example, 
all  fluidextracts  are  of  ioo  per  cent,  strength;  therefore  their 
dose  is  that  of  the  drug,  but  in  liquid  measure,  i.  e.,  each  cubic 
centimeter  is  equivalent  to  one  gram  of  the  drug.  All  potent 
tinctures  are  of  10  per  cent,  strength,  so  their  dose  is  10  times 
that  of  the  fluidextract.  Most  extracts  approximate  5  times  the 
strength  of  the  drug,  hence  have  a  dose  of  one-fifth  as  much. 
For  preparations,  therefore,  the  doses  do  not  have  to  be  carried 
in  mind  as  separate  things,  but  can  be  instantly  calculated  from 
the  percentage  strength  if  the  dose  of  the  drug  itself  is  known. 
On  account  of  pharmacopeial  uniformity,  the  percentage  strength 
is  easily  learned,  as  shown  above.  As  an  example,  take  the  pre- 
parations of  digitalis;  if  the  dose  of  digitalis  is  taken  as  1  grain 
(0.06  gm.),  that  of  the  fluidextract  is  1  minim  (0.06  c.c),  that  of 
the  10  per  cent,  tincture  is  10  minims  (0.6  c.c),  and  that  of  the 
1.5  per  cent,  infusion  is  67  minims,  or  approximately  1  dram 
(4  c.c).  These  amounts  of  the  specified  preparations  each 
represent  the  dose  of  1  grain  of  digitalis. 

5.  Pharmacologic  Action. — How  the  drug  acts.  This  in- 
cludes the  expected  or  usual  action  and  any  unusual  actions,  from 
both  therapeutic  and  toxic  amounts. 

6.  Toxicology. — The  symptoms  and  treatment  in  case  of 
poisoning. 

7.  Therapeutics. — An  extensive  subject  of  immediate  practical 
importance  to  every  physician,  to  be  studied  in  a  general  way 
with  pharmacology,  but  to  be  studied  in  greater  detail  in  con- 
nection with  the  individual  diseases.  It  is  in  therapeutics  that 
there  is  so  much  of  the  traditional,  the  old-fashioned,  the  empiric; 
and  the  crying  need  of  the  medical  profession  is  that  drug 
therapeutics  shall  be  based  directly  upon  thorough  pharmacologic 
knowledge  tried  out  by  clinical  tests. 

8.  Administration. — How  best  to  prescribe  or  administer  the 
remedy. 

p.  Cautions  and  Contraindications. — Conditions  in  which  the 
drug  is  dangerous,  or  may  be  prescribed  only  with  special  cau- 
tion. 

Indication  is  a  term  used  in  medicine  for  the  kind  of  treatment 
"indicated"  or  "pointed  out"  by  the  symptoms  or  disease  of  the 
patient.  We  say,  for  example,  that  "the  indications  in  such  a 
sickness  are  that  the  patient  shall  remain  in  bed,  on  a  milk  diet, 
and  shall  have  a  dose  of  calomel."  Or,  to  put  it  in  another  way, 
we  say  that  "rest  in  bed,  a  milk  diet,  and  calomel  are  indicated," 


THE  PHARMACOLOGIC  ACTION  63 

*.  e.,  "pointed  to"  by  the  symptoms  as  the  means  of  treatment  to 
be  employed.  Contraindication  has  the  opposite  meaning;  it 
is  a  condition  in  which  the  drug  should  not  be  employed. 

THE  PHARMACOLOGIC  ACTION 

In  this  extensive  field  almost  any  kind  of  "aide-memoire" 
will  be  of  value.  It  will,  therefore,  be  our  general  plan  to  take 
up  in  natural  succession  the  actions  of  each  drug  as  follows: 
first,  its  action  independently  of  the  body,  then  its  local  action, 
its  absorption  into  the  system,  its  systemic  action,  its  elimination 
from  or  disposal  by  the  body,  and  finally  its  action  (remote 
local)  as  it  is  being  excreted.  Such  a  scheme  in  detail  is  illus- 
trated in  the  following  chart: 

A.  On  microorganisms  and  enzymes — action  away  from  the 
body,  e.  g.,  antiseptic  action. 

B.  Local  action — 

1.  On  skin  and  adjacent  mucous  membranes — nose,  throat, 
eye,  vagina,  rectum,  urethra,  bladder. 

•external — conjunctiva  and  cornea. 
Eye<^  /pupil. 

internal^  accommodation, 
eyeball  tension. 

2.  On  alimentary  tract: 
Mouth — taste,  appetite,  saliva,  astringency. 

on  contents — acids,  enzymes,  food  sub- 
stances. 
Stomach  \  on     wall — secretion,     movements,    ab- 
sorption  of  food  and  drugs,  pain — 
emetic,  antemetic. 
Intestines — on    contents,     secretion,    movements, 

pain,  character  of  stools. 
Liver,  pancreas — flow  of  bile,  pancreatic  juice,  etc. 

C.  Absorption  of  drug  j  at  what  points  or  not  at  all. 
[  how  rapidly. 

D.  Systemic  action: 
1.  On  the  circulatory  organs: 

Blood — corpuscles,  alkalinity,  coagulability. 

rate — slower,   fas- 
ter, 
fore  e — weaker, 

stronger, 
rhythm  —  regular 
or  irregular. 
Arteries — contracted  or  dilated. 
Arterial  pressure — higher  or  lower. 


Heart — auricles  and  ventricles  \ 


64  PHARMACOLOGY  AND   THERAPEUTICS 

Always  learn  through  what  mechanisms,  and  how,  an  effect 
is  brought  about.  It  is  not  enough  to  know  simply  that  the  heart 
is  faster  or  slower,  or  weaker  or  stronger. 

2.  On  the  respiratory  organs: 

Movements    \      f 
[  rate. 

Bronchi — secretions,  muscle. 

Cough — effect  of  drug  depends  on  whether  cough  is 
due  to  excessive  secretion,  or  lack  of  secre- 
tion, or  sensitiveness  of  throat. 

3.  On  the  nervous  system  and  sense  organs: 

Cerebrum — intellect,  emotions,  sleep,  pain,  motor 
area  (motion,  convulsions,  paralysis). 

Cerebellum — equilibrium. 

Medullary  and  basal  centers — vagus,  vasoconstric- 
tor, respiratory,  heat-regulating,  pupil-dilating, 
secretory,  vomiting. 

Spinal  cord — reflexes  \  ,  .       *         ,     . 

r  [  convulsions,  paralysis. 

Peripheral — sensory,  motor,  secretory. 

Senses — sight,  hearing,  smell,  taste,  touch. 

Eye  {  ?xterna;l  1  (See  Local  Action.) 
J     I  internal  J 

4.  On  muscle  and  bone. 

5.  On  metabolism  and  temperature. 

6.  On  secreting  glands. 
[  male. 

7.  On  genital  organs  \  female —  menstruation,        preg- 
nancy, labor,  etc. 

how  changed  in  body. 

elimination  by  what 
route  and  in  what 
form. 

rapidly  or  slowly — cum- 
ulative. 

F.  Remote  local  action— on  excretory  organs  during  elimina- 

tion—by kidneys,  bladder,  urethra,  skin,  bowels,  lungs, 
mammary  glands;  or  in  urine,  milk,  sweat,  breath,  etc. 

G.  After-effects. 

H.  Untoward  effects — unexpected  or  unusual. 
I.    Tolerance — habit  formation. 

Such  a  scheme  as  the  above  leads  to  completeness  in  the  con- 
sideration of  a  drug's  action. 


E.  Elimination  or  disposal  of  drug 


PART  II 
INDIVIDUAL  REMEDIES 

Since  any  or  all  actions  of  a  drug,  whether  desirable  or  unde- 
sirable, may  result  from  its  administration,  the  proper  use  of  the 
drug  requires  a  knowledge  of  all  its  actions.  Hence  it  is  necessary 
to  study  each  drug  either  as  an  independent  individual  or  as  a 
member  of  a  limited  group  of  drugs  of  nearly  identical  action. 

PROTECTIVES 

A.  DEMULCENTS  AND  EMOLLIENTS 
These  are  agents  which  are  soothing  and  softening  to  epithelial 
tissues.  Their  action  is  essentially  physical  or  mechanical,  and 
is  purely  local.  Those  for  application  to  the  skin  are  called 
"emollients";  those  applied  to  mucous  membranes  are  de- 
mulcents. 

The  emollients  include  the  unctuous  materials,  such  as  lard 
(adeps),  wax  (cera),  spermaceti  (cetaceum),  petrolatum,  cold 
cream  (unguentum  aquae  rosae),  ointment  of  zinc  oxide,  etc.; 
also  cocoa-butter,  olive  oil  and  other  bland  oils,  talcum  powder, 
glycerin,  rose-water,  and  various  soothing  lotions.  The  principle 
of  their  use  is  to  prevent  drying  of  the  epithelium  or  to  soften  and 
protect  dried  or  irritated  tissues.  They  are  employed,  therefore, 
for  chapped  skin,  chafing,  dermatitis,  burns,  etc.  Poultices  and 
hot  fomentations  are  sometimes  considered  emollient,  but  they 
are  best  classed  with  the  hot-water  bag  under  the  heading  Coun- 
terirritants. 

The  demulcents  are  the  mucilaginous  substances,  such  as 
acacia,  tragacanth,  flaxseed  (linum),  slippery  elm  (ulmus  fulva), 
althaea,  sassafras  pith  (sassafras  medulla)  and  Irish  moss  (chon- 
drus  crispus) ;  also  licorice  (glycyrrhiza) ,  sweet  almond  (amyg- 
dala dulcis),  starch  (amylum),  milk,  white  of  egg,  and  the  bland 
fixed  oils  (almond,  olive,  linseed,  cottonseed,  etc.).  In  the  form 
of  lozenges  they  are  employed  in  sore  throat;  in  liquid  form  they 
may  be  taken  by  mouth  for  esophageal  or  stomach  irritation,  as 
following  the  ingestion  of  irritant  poisons,  or  injected  by  rectum 
for  proctitis  or  other  rectal  irritative  conditions.  (For  Starch 
Water,  see  Starch,  in  Part  I.) 

5  6S 


66  PHARMACOLOGY  AND  THERAPEUTICS 

B.  MECHANICAL  APPLICATIONS 
These  are  for  local  application,  and  act  as  protectives  in  a 
purely  mechanical  way.  Such  are:  collodion,  adhesive  plaster, 
liquid  glass  (solution  of  sodium  silicate),  plaster-of-Paris  (dried 
calcium  sulphate),  and  the  various  dusting-powders,  such  as 
starch,  lycopodium,  and  talcum,  the  last  being  a  silicate  of  mag- 
nesium. 

SWEETENING  AGENTS 

These  are  glycerin,  cane-sugar,  syrup  (see  Part  I),  saccharin, 
and  extract  of  malt. 

Saccharin  (benzosulphinid)   is  an  acid  anhydride  with  the 
/S02v 
formula,  C6H4<^  /NH.     With    sodium    bicarbonate  it  dis- 

XCOX 
solves  in  water,  imparting  to  the  liquid  a  peculiar  sweetness  said 
to  be  several  hundred  times  as  great  as  that  of  cane-sugar,  though 
its  flavor  is  not  so  pleasing  as  that  of  sugar.  It  has  been  much 
employed  in  canning  foods,  as  it  is  slightly  antiseptic  and  as  it 
obviates  the  necessity  of  using  the  highly  fermentable  sugar.  It 
is  not  a  food,  and  lacks  the  caloric  value  of  sugar.  Mathews 
and  McGuigan  (1905)  showed  it  to  be  deleterious  in  digestion 
by  ptyalin,  pepsin,  and  trypsin.  In  amounts  of  over  0.3  gm. 
per  day  it  has  been  pronounced  harmful  by  the  government 
Referee  Board  of  Chemists.  It  is  quickly  eliminated  in  the  urine 
in  unchanged  form,  and  the  lethal  dose  for  a  rabbit  is  in  excess  of 
2)4.  drams  (10  gm.).  Its  only  use  in  medicine  is  as  a  sweetening 
agent  for  the  use  of  diabetics,  1  grain  (0.06  gm.)  with  sodium 
bicarbonate  being  employed  instead  of  a  tablespoonful  of  sugar. 

NUTRIENTS 

From  a  pharmacologic  point  of  view,  the  only  substances 
coming  under  this  head  are  gelatin,  sugar  (see  Part  I),  cod-liver 
oil,  and  extract  of  malt. 

COD-LIVER  ODL  (OLEUM  MORRHILSE) 

This  is  a  fixed  oil,  obtained  from  the  fresh  livers  of  Gadus 
morrhua,  and  of  other  species  of  Gadus.  It  contains  faint  traces 
of  iodine  and  bromine  and  sometimes  of  phosphorus,  but  its 
value  in  sickness  seems  to  be  entirely  dependent  upon  its  digesti- 
bility as  a  fat.  In  other  words,  it  is  nothing  but  a  readily  di- 
gestible fat  food,  and  has  no  special  medicinal  virtues.  The 
cheap  oil  obtained  from  putrefactive  livers  contains  various  bases, 


COUNTERIRRITANTS  67 

such  as  choline  and  tyramine.  A  watery  extract  of  such  has  a 
vasoconstrictor  action.     Such  oils  are  no  longer  used. 

Cod-liver  oil  has  a  fishy  odor  and  a  bland,  fishy  taste,  which 
are,  at  least  in  part,  due  to  the  presence  of  free  fatty  acids. 
These  are  abundant  in  the  cheaper  oils,  and  in  the  good  oils  are 
more  readily  produced  in  hot  weather.  As  the  fishy  taste  makes 
cod-liver  oil  especially  nauseating  to  many,  it  is  customary  to 
administer  the  oil  in  admixture  with  the  extract  of  malt,  or  in 
the  form  of  a  sweetened  and  flavored  emulsion.  It  has  been 
shown  experimentally  that  emulsified  oils  are  more  readily  ab- 
sorbable than  the  unemulsified,  especially  by  persons  of  poor 
nutrition,  and  it  is  noted  clinically  that  the  emulsion  is  easier 
to  take  and  is  better  borne  by  the  stomach  than  the  pure  oil. 
It  should  be  given  after  meals  as  an  addition  to  the  regular  food, 
or  two  or  three  hours  after  meals,  to  permit  of  ready  digestion  in 
the  duodenum.     It  should  not  be  given  just  before  meals. 

Cod-liver  oil  is  sometimes  employed  by  inunction  in  cases  of 
severe  malnutrition,  but  the  usefulness  of  this  procedure  is 
seriously  questioned.  On  subcutaneous  injection  Mills  and 
Congdon  (191 1)  found  that  pure  oils  were  slowly  absorbed  by 
starving  animals,  and  more  rapidly  absorbed  when  made  into  an 
emulsion  with  3  to  5  per  cent,  of  lecithin.  It  is  probable  that 
such  an  emulsion  would  be  partly  absorbed  on  rectal  adminis- 
tration. 

Preparations  and  Doses. — Cod-liver  oil — 2  drams  (8  c.c). 

Emulsion,  50  per  cent,  of  oil,  made  with  acacia  and  flavored 
with  sugar  and  wintergreen — 4  drams  (15  c.c). 

Emulsion  with  hypo  phosphites — of  similar  composition  to  the 
above,  but  with  the  addition  of  the  hypophosphites  of  calcium, 
potassium,  and  sodium — 4  drams  (4  c.c). 

EXTRACT  OF  MALT  (EXTRACTUM  MALTI) 
This  is  a  liquid  extract  of  malted  barley.  It  is  of  the  con- 
sistence of  thick  honey,  is  sweet,  and  represents  a  large  per- 
centage of  carbohydrate  nutritive  matter.  It  contains  a  small 
amount  of  the  starch-digesting  ferment,  diastase.  Dose,  }4 
ounce  (15  c.c).  Its  chief  use  is  to  hide  disagreeable  tastes,  as 
of  cascara,  cod-liver  oil,  etc. 


COUNTERIRRITANTS 

These  are  remedies  which,  by  irritation  of  the  skin,  are  in- 
tended to  counter  or  check  deeper-lying  affections.  Counter- 
irritation  is  a  very  old  method  of  treatment,  and  it  still  holds  a 
prominent  place  in  therapeutics.     There  are  several  degrees  of 


68  PHARMACOLOGY  AND    THERAPEUTICS 

skin  irritation  that  may  be  produced,  viz.,  rubefacient,  or  red- 
dening, vesicant,  or  vesicle-producing,  and  epispastic,  or  blistering. 
Beyond  this  an  irritant  may  produce  death  of  tissue.  There  are 
a  few  drugs,  such  as  mercuric  chloride  and  croton  oil,  which  attack 
the  gland-mouths  and  produce  pustules  (pustulant  effect) ,  but  these 
are  not  now  employed  as  counterirritants.  In  therapeutics,  in 
almost  all  cases,  it  is  desirable  to  confine  the  irritation  to  the 
rubefacient  degree.  In  this  the  superficial  vessels  dilate,  the 
skin  becomes  red  and  warm,  and  there  may  be  smarting.  If  the 
application  is  too  strong  or  is  allowed  to  remain  too  long,  little 
vesicles  appear,  and  presently,  coalescing,  form  blisters. 

Blistering  is  very  rarely  employed  as  a  remedial  measure. 
Until  recently  blistering  of  the  gums  by  ammonia  was  a  common 
practice  of  dentists;  and  today  a  fly-blister  over  the  knee-joint 
in  cases  of  large  inflammatory  effusions  is  more  or  less  employed. 
However,  in  almost  all  cases  not  only  is  blistering  not  desirable, 
but  it  is  distinctly  harmful.  For  not  only  is  the  blister  a  painful 
lesion,  requiring  treatment  of  itself,  but  it  effectually  prevents 
further  applications  to  the  skin  at  that  spot.  Hence  the  more 
active  agents,  like  mustard  and  heat,  must  be  carefully  watched, 
especially  when  the  patient  is  suffering  from  severe  pain  or  is 
somnolent  or  comatose.  Unintentional  blistering  frequently  re- 
sults because  of  neglect  to  remove  a  mustard  poultice  before 
going  to  sleep.  In  brunets  an  area  of  blistering  or  even  vesica- 
tion may  be  followed  by  permanent  pigmentation. 

The  mode  of  action  of  counterirritants  has  been  the  subject 
of  much  speculation,  but  the  recognition  in  recent  years  of  a 
relationship  between  the  viscera  and  certain  areas  of  the  skin  and 
body-wall  through  the  nervous  system  has  thrown  much  light 
upon  the  matter.  Dana  (1887),  called  attention  to  "  referred 
pains"  as  being  due  to  the  distribution  of  the  nerves,  and  Head 
(1893)  and  Mackenzie  (1902)  determined  that  tenderness  of  the 
superficial  tissues  might  be  a  manifestation  of  inflammation 
or  injury  of  one  of  the  internal  organs.  Recent  physiologic 
studies  have  shown  that  pain  is  elicited  only  in  structures  supplied 
by  the  cerebrospinal  nervous  system,  and  that  viscera  supplied 
by  sympathetic  nerves  have  no  proper  pain  sense.  The  apparent 
pain  in  inflamed  viscera  is  thus  due  to  a  reflex  effect  through  the 
cerebrospinal  nerves.  Hence  the  tenderness  of  appendicitis  is 
mostly  localized  at  one  point,  though  the  actual  situation  of  the 
appendix  is  very  variable;  the  tenderness  of  cholelithasis  is 
spread  over  an  area  much  greater  than  that  of  the  gall-bladder; 
and  in  pulmonary  tuberculosis  the  superficial  tissues  are  some- 
times so  tender  as  almost  to  preclude  examination  by  percussion. 
Hertz  (1911)  concluded  that  pain  in  disease  of  the  alimentary 


COUNTERIRRITANTS 


69 


tract  maybe  situated  in  the  skin,  muscles,  and  connective  tissues. 
Sherrington  (1909)  demonstrated  that  on  cutting  certain  nerves 
passing  to  the  intestines  and  stimulating  the  central  cut  ends, 
the  abdominal  muscles  contract  in  a  definite  manner.  Also, 
it  is  a  well-known  physiologic  fact  that  pain  tends  to  cause  con- 
traction of  the  splanchnic  arteries. 

These  findings  all  go  to  show  a  very  close  relation,  through 
the  nervous  system,  between 
the  tissues  of  the  body- wall 
and  the  contained  viscera, 
and  tend  to  explain  how  ir- 
ritation of  a  superficial  area 
may  have  a  decided  effect 
upon  a  deep-lying  or  even 
remote  viscus  which  is  in  no 
way  in  direct  connection  or 
contact  with  the  irritated 
area.  In  this  way  may  be 
understood  the  expulsion  of 
flatus  by  the  intestines  as  the 
result  of  a  turpentine  stupe 
applied  to  the  abdomen, 
though  the  intestines  have  no 
direct  anatomic  connection 
with  the  anterior  abdominal 
wall ;  or  the  effect  of  a  mus- 
tard foot-bath  in  pelvic  con- 
gestion; or  of  a  mustard  paste 
on  the  chest  in  pleurisy  or 
pneumonia.  It  has  been 
demonstrated  also  that  cold 
and  heat  act  reflexly  and  not 
directly,  for  the  superficial 
application  of  an  ice-bag  or  a 
hot-water  bag  has  little  if 
any  effect  upon  the  tempera- 
ture of  a  deep-lying  viscus. 

As  working  theories,  Head  and  Hertz  adopt  the  segmental 
relation,  i.  e.,  that  the  spinal  cord  and  brain  are  in  regular  seg- 
ments, and  that  a  lesion  affecting  a  nerve  from  a  given  segment 
affects  all  the  nerves  whose  centers  are  in  that  same  segment. 
"Head's  areas,"  mapped  out  on  the  skin  by  Head  as  being  the 
areas  of  tenderness  in  the  various  visceral  affections,  have  not, 
however,  been  at  all  constant,  and  Mackenzie  has  pointed  out 
that  in  visceral  lesions  pain  and  tenderness  do  not  appear  in  the 


Fig.  r. — Areas  in  which  pain  is  some- 
times felt:  (A)  In  cardiac  affections;  (B) 
in  affections  of  the  stomach;  (C)  in  affec- 
tions of  the  liver,  stomach,  or  duodenum; 
(D)  in  affeccions  of  rectum  or  uterus  (after 
James  Mackenzie,  in  "Symptoms  and 
Their  Interpretation"). 


7<D  PHARMACOLOGY   AND    THERAPEUTICS 

whole  distribution  of  any  one  segment,  but  in  limited  areas  in 
the  distribution  of  two  or  several  segments.  Therefore,  Macken- 
zie suggests  a  regional  relation  rather  than  a  segmental  one.  The 
good  action  of  these  reflexes  may  be  the  result  of  a  conferred 
hypersensitiveness  to  stimuli,  to  reflex  changes  in  the  circulation, 
or  to  other  so  far  unknown  effects. 

Rubbing  the  back  will  sometimes  distinctly  affect  the  viscera, 
and  Mackenzie's  picture  herewith  suggests  a  reason  for  the  suc- 
cess, in  some  instances,  of  the  osteopathic  plan  of  manipulating 
the  spine  and  its  neighborhood. 

That  counterirritation  may  act  in  other  ways  is  also  possible, 
for  it  is  well  known  to  every  one  that  pain  in  a  sensitive  place 
results  in  a  diminished  sense  of  pain  in  a  less  sensitive  region. 
It  is  probable,  also,  that  the  psychic  suggestive  effect,  as  of  a 
thermocautery,  may  at  times  be  important,  and  that  in  the  treat- 
ment of  muscular  or  other  tissues  in  direct  contact  with  the  skin 
changes  in  the  local  blood-supply  may  account  for  the  remedial 
effect.  In  this  connection  it  is  of  interest  that  Lazarus-Barlow 
has  shown  that  a  muscle  on  the  same  side  as  a  blister  has  a  higher 
specific  gravity  than  the  corresponding  muscle  on  the  unblistered 
side.  And  Wechsberg  has  demonstrated  that  when  abscesses 
were  experimentally  produced  in  rabbits'  legs,  they  were  less 
extensive  and  healed  more  rapidly  on  the  side  to  which  counter- 
irritants  were  applied.  Oliver  found  that  a  mustard  paste  over 
the  liver  sent  the  blood-pressure  from  105  to  135,  and  Roth,  that 
a  large  hot  application  to  chest  and  abdomen  sent  up  the  pressure 
about  8  mm.  in  each  of  two  cases.  But  Wood  and  Weisman 
(191 2)  find  that  irritation  of  the  skin  of  the  hand  by  a  mustard- 
bath  just  short  of  producing  dermatitis  does  not  materially 
increase  the  rate  of  blood-flow  in  the  hand,  the  skin  redness 
being  presumably  not  accompanied  by  a  change  in  the  caliber 
of  the  deep-lying  arterioles. 

We  may  sum  up,  then,  by  repeating  that  the  good  effects  of 
counterirritation  may  be  due  to:  (1)  A  segmental  or  regional 
nervous  relation  between  superficial  tissues  and  the  viscera. 
(2)  The  countering  effect  of  a  superficial  pain  over  a  deep-seated 
one.     (3)  A  direct  circulatory  effect.     (4)  A  psychic  effect. 

Preparations. — The  more  commonly  employed  counter- 
irritant  measures  are:  heat,  cold,  dry-cupping,  and  drugs. 

Heat  is  applied  as  an  electric  pad,  a  hot-water  bottle,  a  hot 
stone  or  flat-iron  wrapped  in  cloth,  or  a  poultice,  when  the  desire 
is  to  apply  something  that  will  keep  hot  a  long  time.  For  a 
sudden  application  of  extreme  heat  the  thermocautery  or  the 
stupe  may  be  employed.  A  stupe  is  a  towel  wrung  out  of  very 
hot  water;    a  turpentine  stupe  is  made  by  sprinkling  15  or  20 


COUNTERIRRITANTS  7 1 

minims  of  oil  of  turpentine  on  the  hot  towel.  In  the  use  of  the 
thermocautery  for  counterirritant  effect  the  skin  should  not  be 
seared,  but  merely  reddened  by  the  rapid  passage  over  it  of  the 
red-hot  iron  or  platinum  point.  Poultices  may  be  made  of  lin- 
seed meal,  bread,  flour,  bran,  or  hops  boiled  with  water  and 
wrapped  in  cheese-cloth  or  any  thin  fabric.  The  clay  poultice 
(cataplasma  kaolini,  U.  S.  P.)  has  kaolin  and  glycerin  as  its  basis, 
with  added  small  amounts  of  boric  acid,  oil  of  peppermint,  methyl 
salicylate,  and  thymol.  It  has  practically  no  absorption  power 
for  water,  but  acts  largely  by  its  heat  (Roth);  so  for  use  it  is 
heated  in  its  container  and  smeared  over  the  part  with  a  knife 
or  stick.  A  proprietary  name  for  this  is  "antiphlogistine." 
Roth  (1905)  showed  that  it  had  less  power  as  a  counterirritant 
and  retained  heat  for  a  shorter  time  than  a  flaxseed  poultice. 

Cold  is  for  the  most  part  secured  by  an  ice-bag  or  ice-water 
coil.  It  has  been  ascertained  that  locally  applied  heat  or  cold 
does  not  affect  the  temperature  of  the  viscera  to  any  extent,  and 
that  their  value  in  internal  inflammations  is  not  antiphlogistic, 
but  reflex.  Cold  is  often  applied  directly  to  an  injured  or  in- 
fected area  with  the  idea  of  quieting  the  inflammation  and  of 
checking  the  activity  of  bacteria,  but  it  also  lessens  the  resistance 
of  the  tissues  of  the  patient,  and  by  so  doing  may  do  more  harm 
than  good.  Fauntleroy  (191 2)  believes  that  in  some  cases  of 
appendicitis  the  ice-bag  is  responsible  for  poor  walling-off  of  the 
lesion  and  poor  resistance  on  the  part  of  the  patient,  as  shown  by 
the  failure  of  the  leukocytes  to  increase  much  above  the  normal. 

Dry-cupping  is  a  process  of  suction  applied  to  the  skin  by 
means  of  specially  made  cups  or  small  tumblers  in  which  a 
vacuum  is  created.  There  are  several  methods  of  obtaining  the 
vacuum,  such  as  swabbing  out  the  cup  with  a  cotton  probe  dipped 
in  alcohol  and  then  lighting  the  alcohol,  or  igniting  some  cotton 
stuck  in  the  bottom  of  the  cup.  The  cup  must  be  instantly  ap- 
plied; and  in  order  that  it  may  hold  and  perform  its  suction,  its 
application  must  be  in  a  region  where  the  tissues  are  soft  enough 
to  be  drawn  upon.  Care  should  be  taken  not  to  burn  the  patient 
and  not  to  leave  the  cups  on  long  in  one  place.  Dry-cupping  is 
not  now  much  employed  because  of  its  awkwardness,  but  in 
extreme  cases,  as  in  edema  of  the  lungs  or  suppression  of  urine, 
may  be  resorted  to. 

Drugs. — These  are  all,  in  the  nature  of  the  case,  general 
protoplasmic  irritants.  The  rubefacients  are:  camphor,  menthol, 
and  chloral  hydrate,  any  two  of  which  solids,  when  mixed  together, 
become  liquefied;  the  spirit  and  liniment  of  camphor,  alcohol, 
chloroform,  methyl  salicylate  (the  liquid  stearopten  which  composes 
over  90  per  cent,  of  oil  of  wintergreen  or  oil  of  birch),  oil  of  tur- 


72  PHARMACOLOGY  AND    THERAPEUTICS 

pentine,  tincture  of  iodine,  ammonia,  capsicum,  and  mustard. 
The  epispastics  are :  ammonia  water  (used  by  dentists  for  blister- 
ing the  gums)  and  cantharides  cerate. 

Mustard  (sinapis)  is  the  ground  seed  of  black  mustard 
(sinapis  nigra).  Its  use  depends  upon  the  development  of  an 
irritant  volatile  oil  when  the  mustard  flour  is  mixed  with  water. 
(See  Glucosides,  Part  I.)  It  may  be  employed  in  the  form  of  a 
mustard-leaf  (charta  sinapis)  dipped  in  tepid  water,  or  as  a  thin 
mustard  paste  made  by  wetting  a  mixture  of  mustard  and  flour 
with  tepid  water  and  wrapping  in  cheese-cloth.  For  an  adult 
the  paste  may  be  made  of  one  part  of  mustard  to  two  or  three  of 
flour,  according  to  the  sensitiveness  of  the  skin;  for  a  child,  one 
part  to  four  or  five  of  flour.  A  mustard  paste  usually  reddens 
sufficiently  in  ten  to  thirty  minutes,  and  its  effect  must  be 
watched  to  prevent  blistering.  As  soon  as  the  skin  is  thoroughly 
reddened  the  mustard  should  be  removed.  Sometimes,  with  the 
idea  of  preventing  blistering,  white  of  egg  is  mixed  with  the  paste, 
or  vaseline  is  smeared  over  the  skin  at  the  site  of  application. 
Whether  such  measures  are  efficacious  or  not  we  are  unable 
to  say.  In  pelvic  congestion  with  suppressed  menstruation  a 
mustard  foot-bath  is  sometimes  employed.  It  is  made  by  adding 
a  tablespoonful  of  mustard  to  four  quarts  of  warm  water.  A 
mustard-bath  for  infants  is  prepared  of  half  this  strength.  In 
all  mustard  preparations  very  hot  water  should  not  be  used,  as 
this  destroys  or  retards  the  activity  of  the  enzyme  which  forms 
the  irritant  volatile  oil.  The  enzyme  is  destroyed  at  6o°  C. 
(1400  F.).  It  is  to  be  borne  in  mind  that  the  "hotness"  of  a 
mustard-bath  should  be  entirely  due  to  the  mustard  oil  developed, 
and  not  to  its  temperature  as  recorded  by  the  thermometer. 
Cases  of  poisoning  by  mustard  give  the  symptoms  of  volatile 
oil  poisoning.     (See  Carminatives.) 

Cantharides  (cantharis)  is  the  dried  and  powdered  brilliant 
green  beetle,  Cantharis  vesicatoria,  or  Spanish  fly.  Its  active 
constituent  is  cantharidin,  an  acid  anhydride  which  forms 
soluble  salts  with  alkalies.  The  "  fly-blister "  is  a  piece  of  ad- 
hesive plaster  spread  with  cantharides  cerate.  About  its  only 
employment  is  in  large  inflammatory  collections  of  fluid  in  the 
knee-joint,  as  in  acute  rheumatism.  A  fly-blister  about  two 
inches  in  diameter  is  applied  to  the  skin  for  twenty  minutes, 
then  removed,  and  replaced  by  a  flaxseed  poultice.  A  large 
amount  of  serum  collects  beneath  the  skin  and  is  removed  by 
pricking  the  skin. 

Internally,  the  10  per  cent,  tincture  has  been  employed  as  an 
emmenagogue  in  dose  of  5  minims  (0.3  c.c).  From  its  use  to 
produce  abortion,  and  its  administration  with  the  fancied  purpose 


CAUSTICS    (ESCHAROTICS)  73 

of  stimulating  sexual  feeling,  many  poisoning  cases  have  resulted. 
It  is  a  violent  irritant,  the  symptoms  following  large  or  undiluted 
doses  being  local  irritation  in  mouth,  esophagus,  stomach,  and 
intestines,  resulting  in  inflammation,  blistering,  or  ulceration, 
with  vomiting,  diarrhea,  bloody  stools,  and  cramps.  The  kid- 
neys and  bladder  also  show  intense  inflammation,  with  bloody 
urine  or  suppression  of  the  urine.  There  is  sometimes  priapism. 
Pregnant  women  may  abort.  The  patient  may  go  into  profound 
collapse,  resulting  in  death.  The  treatment  is  symptomatic, 
demulcents  being  administered  by  mouth  and  rectum,  and  col- 
lapse treated  as  described  later. 

Therapeutics  of  Counterirritants. — i.  To  relieve  pain — mus- 
cular, neuralgic,  and  joint  pains,  as  well  as  those  associated  with 
visceral  affections  (pleurisy,  cardiac  pain,  biliary  and  intestinal 
colic,  and  dysmenorrhea). 

2.  To  relieve  congestion  and  inflammation — as  in  the  case  of 
inflamed  lymph-nodes,  pelvic  congestion,  and  pneumonia. 

3.  To  promote  absorption — as  of  serous  effusions  in  the  pleural 
or  peritoneal  cavities  or  joints,  in  hydrocele,  and  in  bruises  or 
hematomata. 

4.  To  overcome  tympanites — as  in  the  use  of  the  stupe  in  ty- 
phoid fever  or  post-operative  intestinal  paralysis. 

5.  To  overcome  collapse — as  in  the  use  of  mustard-bath  or 
alternating  hot  and  cold  plunges  for  infants. 

6.  To  check  nose-bleed — ice  to  the  back  of  the  neck. 

7.  To  relieve  cerebral  congestion — as  the  ice-bag  in  headache, 
delirium,  meningitis,  etc.,  or  the  menthol  pencil  inheadache. 

Cautions. — Debility  and  old  age,  in  which  conditions  irritants 
of  all  kinds  tend  to  be  depressing. 

CAUSTICS  (ESCHAROTICS) 

These  are  substances  which  act  by  causing  the  death  of  tissue. 
They  may  destroy  by  consuming  the  tissue,  as  in  the  case  of  sul- 
phuric acid,  or  by  precipitating  protoplasm,  as  by  phenol,  or 
by  causing  an  inflammation  which  results  in  a  slough,  as  in  the 
case  of  arsenic.     The  caustics  are: 

1.  Acids. — Sulphuric,  nitric,  glacial  acetic,  trichloracetic. 

2.  Alkalies. — The  hydroxides  of  potassium,  sodium,  and  cal- 
cium (lime). 

3.  Metallic  Salts. — Silver  nitrate  (lunar  caustic),  copper  sul- 
phate (bluestone).  zinc  chloride,  burnt  alum,  chromium  trioxide 
(chromic  acid),  arsenic  trioxide  (arsenous  acid). 

4.  Carbon  dioxide,  liquid  or  solid. 

5.  Phenol. 


74  PHARMACOLOGY  AND  THERAPEUTICS 

Sulphuric  acid  chars;  nitric  acid  changes  the  part  to  yellow, 
and  all  acids  act  by  abstracting  water  and  neutralizing  the  al- 
kalinity of  the  tissues.  They  are  direct  irritants,  even  when 
diluted.  The  alkalies  abstract  water  and  saponify  the  fatty 
substances  of  protoplasm;  they  are  very  penetrating,  and  make 
ulcers  which  are  slow  to  heal.  Chromium  trioxide  comes  in  the 
form  of  deliquescent,  dark  reddish  crystals,  which  decompose 
or  explode  on  the  addition  of  glycerin,  alcohol,  or  other  organic 
substances.  Among  chromate  workers  perforation  of  the  nasal 
septum  is  the  rule.  It  results  from  inhalation  of  the  dust. 
There  are  also  a  number  of  caustic  substances,  such  as  mercuric 
bichloride,  which  are  not  used  as  such  in  therapeutics. 

Toxicology. — When  caustic  acids  or  alkalies  are  swallowed, 
they  burn  and  denude  the  tissues  of  mouth,  esophagus,  and  stom- 
ach, and  produce  shock.  To  neutralize  acids,  mild,  non-car- 
bonated alkalies  may  be  used,  such  as  diluted  lime  or  magnesia; 
the  carbonated  alkalies  set  free  too  much  gas.  To  neutralize 
alkalies,  vinegar  and  lemon-juice  are  good.  For  the  burns,  de- 
mulcents, such  as  olive  oil,  lard,  white  of  egg,  milk,  etc.,  are  indi- 
cated.    (For  poisoning  by  metallic  salts  and  phenol,  see  later.) 

Therapeutics. — To  remove  exuberant  granulations,  small 
polypi,  warts,  and  hypertrophied  soft  tissues,  as  in  the  nose. 
Caustics  are  now  very  little  employed  except  for  application  to 
small  and  superficial  areas.  Carbon  dioxide,  in  liquid  form  or  in 
sticks,  has  been  used  to  remove  nevi,  and  in  the  treatment  of 
lupus,  sluggish  ulcers,  epitheliomata,  and  leprosy. 

To  cauterize  is  to  sear  the  tissues.  It  may  be  done  with  the 
thermocautery  or  electric  cautery,  or  by  nitric  acid,  phenol 
(carbolic  acid),  or  lunar  caustic.  Phenol  is  adapted  for  infected 
cavities  or  sinuses,  the  area  being  afterward  washed  with  alcohol 
to  check  further  penetration  of  the  phenol.  For  dog-bites, 
Bartholow,  of  the  New  York  Department  of  Health  (191 1)  recom- 
mends the  following  in  the  order  of  their  merit,  viz. :  (1)  Fuming 
nitric  acid;  (2)  silver  nitrate;  (3)  the  actual  cautery.  The 
employment  of  the  thermo-  or  electric  cautery  for  the  removal  of 
tissue  is  quite  different  from  its  counterirritant  use,  in  which  the 
skin  should  not  be  seared. 

SCARLET  RED 
Scarlet  red  is  a  name  given  to  several  different  dye-stuffs,  but 
that  recommended  for  medicinal  use  is  toluol-azotoluol-azobeta- 
naphthol .  It  is  known  as  ' '  Scarlet  R , "  and  is  marketed  in  powder 
form  and  in  8  per  cent,  ointment.  From  the  many  published 
reports  it  would  seem  to  have  a  marked  power  to  stimulate  the 
growth  of  epithelium  over  sluggish  wounds  and  ulcers.     Davis, 


THIOSINAMINE — FIBROLYSIN;    CHRYSAROBIN  75 

of  Johns  Hopkins  (191 1,  191 2),  records  very  rapid  covering  of 
the  surface  of  sluggish  sores  with  epithelium  having  the  macroscopic 
and  microscopic  appearances  of  normal  skin.  On  the  injection 
into  dogs  and  rabbits  of  a  i  per  cent,  solution  in  oil  he  found  it 
non-irritating  and  non-toxic,  though  it  was  disseminated  through 
the  body  and  stained  the  fatty  tissues.  In  man  he  gave  it  by 
mouth,  amounts  of  32  grams,  63.3  grams,  and  66.5  grams  in 
about  four  weeks  producing  no  symptoms,  and  being  apparently 
unabsorbed,  as  they  did  not  stain  the  fat  of  the  body.  He 
therefore  recommends  its  use  in  gastric  ulcer. 

THIOSINAMINE— FIBROLYSIN 

Thiosinamine,  or  allyl  sulphocarbamide,  is  soluble  in  3  parts 
of  alcohol.  It  is  decomposed  by  water,  though  this  change  is 
retarded  by  glycerin.  Fibrolysin  is  the  trade  name  for  a  sterile 
aqueous  solution  of  a  double  salt  of  thiosinamine  and  sodium 
salicylate.  It  is  marketed  in  ampules  of  2.3  c.c.  of  solution, 
representing  3  grams  (0.2  gm.)  of  thiosinamine. 

Thiosinamine,  in  dose  of  1.3  grams  (0.06-0.2  gm.),  is  ad- 
ministered by  rectum  or  vagina  in  suppositories,  or  subcuta- 
neously  in  10  per  cent,  freshly  prepared  glycerin-water  suspension 
or  in  15  per  cent,  alcoholic  solution.     It  is  very  irritant  locally. 

Fibrolysin  is  employed  subcutaneously,  intramuscularly,  or 
intravenously.  The  injections  are  given  at  intervals  of  one  to 
three  days,  in  some  cases  as  many  as  60  injections  being  given. 
It  is  less  irritant  locally  than  thiosinamine.  The  action  of  the 
drug  is  to  soften  scar  tissue,  and  perhaps  to  promote  its  absorp- 
tion. Starkenstein  states  that  it  favors  the  hydrolysis  of  collagen 
into  gelatin.  There  are  many  clinical  reports  of  its  value  in 
hypertrophied  scars  of  the  skin;  in  strictures  of  esophagus, 
rectum,  and  urethra;  in  fibrous  ankylosis;  in  arthritis  defor- 
mans; in  sciatica;  in  opacities  of  the  cornea,  etc.  F.  Ehrlich 
has  employed  it  with  success  to  loosen  the  adhesions  of  small 
epigastric  and  umbilical  hernias.  Such  a  drug  would  seem  to  be 
a  desideratum  in  therapeutics,  yet  it  has  limitations  in  its  power 
to  affect  scar  tissue,  and  its  failures  are  frequent.  It  is  contra- 
indicated  in  active  inflammatory  conditions;  in  tuberculosis 
where  connective-tissue  formation  is  desired,  and  in  ulceration 
of  the  alimentary  tract.  It  is  said  to  be  useless  in  corneal 
opacities  of  long  standing. 

CHRYSAROBIN 

Chrysarobin  is  a  neutral  principle  extracted  from  Goa  powder, 
a  substance  found  deposited  in  clefts  or  cavities  of  the  wood  of 
the  araroba  tree  of  Brazil.     It  is  an  orange-yellow  powder,  taste- 


76  PHARMACOLOGY  AND  THERAPEUTICS 

less  and  odorless,  but  irritating  to  mucous  membranes  if  con- 
tinuously applied.  Practically  its  only  use  at  present  is  in 
psoriasis,  the  5  per  cent,  ointment  being  employed.  This  is  not 
used  about  the  face,  as  it  may  cause  irritation  of  eyes,  nose,  and 
mouth. 

THE  DIGESTIVE  FERMENTS 

PEPSIN 

Pepsin  (pepsinum)  is  an  enzyme  usually  obtained  from  the  fresh 
mucous  membrane  of  the  hog's  stomach.  It  is  almost  entirely 
soluble  in  50  parts  of  water,  and  more  so  in  water  acidulated  with 
hydrochloric  acid.  It  acts  in  a  weakly  acid  medium  to  change  the 
insoluble  proteins  of  the  food  into  soluble  protein.  It  is  destroyed 
by  0.01  per  cent,  sodium  hydroxide  (Sollmann),  and  it  is  inhibited 
by  strong  acid,  human  pepsin,  for  example,  ceasing  to  act  when 
the  hydrochloric  acid  reaches  0.3  per  cent.  By  the  U.S. P.  test 
it  must  be  able  to  change  3000  times  its  weight  of  coagulated  egg- 
albumin  into  soluble  protein.  In  other  words,  one  grain  of  pepsin 
can  digest  at  least  6J/4  ounces  of  coagulated  egg-albumin.  Dr. 
Gies  has  told  me  of  a  specimen  in  existence  200  times  as 
powerful  as  this.  The  U.  S.  P.  test  calls  for  digestion  at  125. 6° 
F.  (5 20  C.)  for  two  and  one-half  hours  in  water  containing  one 
part  of  absolute  hydrochloric  acid  in  3000. 

Pepsin  is,  therefore,  a  highly  powerful  substance;  and  it 
would  be  a  very  important  therapeutic  agent  were  it  not  for  the 
fact  that  in  almost  all  classes  of  digestive  disturbances  it  is  a 
superfluous  remedy.  For  by  extensive  tests  with  human  gastric 
contents  it  has  been  found  that,  except  in  the  not  very  numerous 
cases  of  achylia  gastrica  with  atrophy  of  the  gastric  mucous 
membrane,  the  stomach  rarely  fails  to  secrete  its  specific  ferments. 
Hence  its  only  use  as  a  digestive  agent  is  in  atrophic  cases,  and 
in  these  it  is  not  always  efficient.  (See  Pancreatin.)  It  may  be 
given  in  capsules,  5  grains  (0.3  gm.)  at  the  beginning  of  a  meal  and 
5  grains  at  the  end,  with  hydrochloric  acid  in  proper  dilution. 

Pepsin  regularly  contains  some  rennin;  its  solutions,  there- 
fore, will  coagulate  milk. 

PANCREATIN 
Pancreatin  (pancreatinum)  is  usually  obtained  from  the  fresh 
pancreas  of  the  hog  or  ox.  It  contains  the  specific  ferments  of 
the  pancreas,  and  represents  its  external  secretion.  There  is  no 
evidence  that  it  also  represents  the  internal  secretion,  and  it  has 
no  power  to  check  pancreatic  diabetes.  Its  notable  actions  are 
those  of  the  enzymes,  trypsin,  amylopsin,  and  steapsin.  It  acts 
best  in  an  alkaline  medium. 


PANCREATIN 


77 


The  Pharmacopoeia  gives  tests  of  its  protein  and  starch- 
digesting  power.  It  specifies  that  i  grain  of  pancreatin  with 
5  grains  of  sodium  bicarbonate  must  be  able  to  peptonize 
completely  3  ounces  of  cow's  milk  at  100.40  F.  (380  C.)  in 
thirty  minutes;  that  is,  it  must  change  the  proteins  so  that  the 
milk  will  not  coagulate  on  the  addition  of  nitric  acid.  It  further 
specifies  that  this  amount  of  pancreatin  (1  grain)  must  be  able 
to  change  28  times  its  weight  of  starch  into  substances  soluble  in 
water,  i.  e.,  into  dextrin,  maltose,  etc.  Hence  pancreatin  would 
be  another  important  therapeutic  agent,  but  that,  like  pepsin, 
it  is  seldom  needed  in  therapeutics. 

When  the  secretion  of  gastric  juice  fails,  as  in  achylia,  the 
choice  is  left  open  of  administering  pepsin  and  hydrochloric 
acid,  or  pancreatin  and  sodium  bicarbonate,  to  bring  about  di- 
gestion in  the  stomach.  In  this  condition  free  passage  from  the 
stomach  to  the  intestines  is  desirable,  and  any  interference  with 
the  emptying  of  the  stomach  is  bad.  Hence  in  a  number  of 
cases  sodium  bicarbonate  and  pancreatin  are  to  be  preferred, 
as,  unlike  hydrochloric  acid,  they  do  not  induce  closure  of  the 
pylorus. 

In  the  milder  form  of  chronic  pancreatitis  with  emaciation, 
and  in  the  very  rare  cases  of ''pancreatic  infantilism,"  a  condi- 
tion of  stunted  growth,  and  chronic  diarrhea,  excellent  results  are 
recorded  from  the  administration  of  pancreatin.  Byron  Bram- 
well  reported  a  boy  of  nineteen  with  development  arrested  from 
the  age  of  eleven  and  chronic  diarrhea  for  the  last  nine  years. 
He  was  bright  and  intelligent  and  not  a  cretin.  His  urine  was 
free  from  sugar.  Under  the  influence  of  pancreatin  by  mouth 
he  grew  five  inches  in  two  years  and  gained  22  pounds.  Rentoul 
had  a  girl  of  eighteen,  in  a  similar  condition  of  stunted  develop- 
ment, gain  9J/2  pounds  and  grow  2  inches  in  less  than  five  months, 
at  the  same  time  showing  decided  sexual  development  and  general 
improvement.  Thompson  reports  two  such  cases.  They  are 
very  rare.  These  results  may  be  due  not  to  the  digestive  power, 
but  to  an  effect  which  the  pancreatin  may  exert  upon  the  ac- 
tivity of  other  glands,  for  instance,  the  thyroid.  Indeed,  be- 
cause of  the  discovery  of  a  probable  antagonism  between  the 
internal  secretions  of  pancreas  and  thyroid,  pancreatin  has  been 
employed  in  hyperthyroidism. 

In  chronic  pancreatitis  pancreatin  has  been  of  uncertain 
value,  and  in  checking  a  pancreatic  diabetes  has  proved  a  failure. 
But  in  some  cases  it  has  overcome  the  failure  of  fat  and  protein 
digestion  which  regularly  accompanies  pancreatitis,  and  so  has 
resulted  in  improved  nutrition  and  the  disappearance  of  pan- 
creatitic  emaciation.     In   some   cases   of   fat   indigestion   with 


78  PHARMACOLOGY  AND   THERAPEUTICS 

diarrhea,  not  especially  attributable  to  the  pancreas,  as  in  tu- 
berculosis, pancreatin  has  checked  the  diarrhea  and  promoted 
nutrition.  The  trypsin  of  pancreatin  is  destroyed  by  pepsin 
in  0.1 12  per  cent,  hydrochloric  acid  (Sollmann),  and  is  injured 
by  0.056  per  cent,  of  hydrochloric  acid  alone;  hence,  except  in 
cases  of  achylia  gastrica,  it  should  be  given  after  the  stomach 
digestive  period,  i.  e.,  about  four  hours  after  meals. 

The  chief  use  of  pancreatin,  however,  is  not  as  a  remedy  for 
internal  administration,  but  as  an  agent  for  peptonizing  milk 
(and  other  protein  foods)  for  invalids.  A  formula  for  peptonizing 
milk  is: 

Pancreatin gr.  v  (0.3  gm.) 

Sodium  bicarbonate gr.  xx  (1.3  gm.) 

Water B  iv  (1 20  c.c.) 

Milk Oj  (480  c.c.) 

This  is  kept  warm  at  a  temperature  never  hotter  than  the 
hand  can  bear  continuously  without  discomfort  (1150  F.). 
At  the  end  of  fifteen  minutes  enough  peptones  are  present  to  give 
the  mixture  a  faintly  bitter  taste.  At  the  end  of  an  hour,  or 
sometimes  in  half  an  hour,  the  milk  is  fully  peptonized,  that  is, 
will  not  coagulate  on  the  addition  of  nitric  acid;  it  is  changed  in 
appearance  and  has  a  decidedly  bitter  taste.  For  gavage  or  rectal 
feeding  milk  should  be  "fully  peptonized";  for  administration 
by  mouth  it  is  usually  peptonized  only  fifteen  or  twenty  minutes 
because  of  the  taste.  At  the  end  of  the  desired  time  it  should  be 
brought  quickly  to  the  boiling-point  to  destroy  the  enzyme,  and 
should  then  be  kept  on  ice.  The  "cold  method"  of  adding  the 
pancreatin  and  sodium  bicarbonate  and  allowing  the  milk  to 
stand  without  warming  is  uncertain  and  unscientific. 

Pepsin  preparations  are  not  suitable  for  peptonizing,  for  they 
invariably  contain  the  coagulating  enzyme,  rennin,  and  conse- 
quently coagulate  the  milk. 

RENNIN  (Rennet) 
Rennin  is  not  a  digestant,  but  is  the  milk-coagulating  ferment 
of  the  gastric  juice.  It  is  obtained  from  the  mucous  membrane  of 
the  fourth  stomach  of  the  calf.  Under  its  influence  the  case- 
inogen  of  milk  changes  to  paracasein,  and  the  latter  takes  cal- 
cium and  forms  an  insoluble  curd.  The  calcium  is  usually  fur- 
nished by  the  calcium  phosphate  of  the  milk,  but  occasionally 
must  be  supplied  by  the  addition  of  a  small  amount  of  calcium 
chloride  or  lime-water.  The  ordinary  rennin  curd  contains  13 
per  cent,  more  calcium  than  the  curd  of  hydrochloric  acid 
(Harris),  and  is  tougher  and  more  cohesive,  though  less  dense 


DIASTASE  79 

and  more  readily  acted  upon  by  pepsin.  If  the  stomach-con- 
tents are  highly  acid  or  more  than  very  slightly  alkaline,  the 
rennet  will  not  act.  Hence  if  sodium  bicarbonate  or  more  than 
a  very  little  lime-water  is  added  to  milk,  no  coagulation  takes 
place  at  all ;  and  in  marked  cases  of  hyperacidity  the  curd  formed 
is  the  dense  hydrochloric  acid  curd  and  not  that  of  rennet.  Its 
action  is  retarded  by  agitation  unless  in  the  presence  of  hydro- 
chloric acid  (Bernegau).  It  has  been  found  to  coagulate  from 
5000  to  166,000  times  its  weight  of  milk. 

The  use  of  rennet  in  medical  practice  is  to  prepare  junket 
and  whey.  Junket  is  the  whole  coagulated  milk,  and  is  a  valu- 
able food  for  invalids.  It  is  prepared  by  adding  the  commercial 
liquid  rennet,  or  essence  of  pepsin,  or  junket  tablets  dissolved  in 
water,  to  barely  warm  milk,  and  setting  aside  till  the  clotting 
takes  place.  The  process  is  retarded  if  the  milk  is  hot.  The 
junket  may  be  eaten  plain  or  with  cream  and  sugar;  it  may  be 
flavored  with  sherry,  nutmeg,  etc. 

Whey  is  the  liquid  portion  of  the  milk  after  the  rennet  curd 
is  removed.  It  is  obtained  by  breaking  up  the  junket  and  strain- 
ing through  cheese-cloth  or  linen.  It  contains  some  of  the  rennin 
ferment,  a  small  amount  of  soluble  protein  (lactalbumin),  a 
slight  amount  of  fat,  about  4  per  cent,  of  milk-sugar,  and  the 
salts  of  the  milk  with  the  exception  of  the  calcium  phosphate. 
It  is  used  as  a  nearly  protein-free  diluent  of  milk  in  infant- 
feeding.  Before  it  is  added  to  milk  it  should  be  brought  to  the 
boiling-point  to  destroy  the  rennin;  otherwise  it  will  coagulate 
the  new  milk. 

Rennet  is  used  very  extensively  in  cheese-making  and  in 
the  preparation  of  junket  for  the  table. 

DIASTASE 

Diastase  is  the  starch-digesting  agent  of  barley  malt,  changing 
hydrolized  or  cooked  starch  to  dextrin  and  maltose.  It  has  also 
some  power  to  hydrolyze  starch.  It  acts  in  a  neutral  or  slightly 
acid  medium,  is  retarded  in  its  activity  by  alkalies  (Chittenden 
and  Ely,  and  Kellerman),  and  is  destroyed  by  strong  acids.  Its 
digestive  power  is  seldom  needed  in  therapeutics,  except  possibly 
in  pancreatic  disease,  or  where  for  some  obscure  reason  starch 
digestion  is  definitely  defective. 

The  extract  of  malt  is  prepared  by  extracting  barley  malt 
with  water  and  evaporating  to  a  thick,  honey-like  consistence. 
It  contains  much  maltose  and  other  nutritive  matter  and  a  little 
diastase.  As  its  diastatic  activity  is  not  very  great,  it  is  really 
nothing  but  a  form  of  carbohydrate  food.     Owing  to  its  sweet- 


So  PHARMACOLOGY  AND   THERAPEUTICS 

ness  and  thick  consistence  it  is  a  good  vehicle  for  cod-liver  oil, 
cascara,  and  other  strong-tasting  drugs. 

There  are  also  marketed  some  "extract  of  malt"  preparations 
which  are  really  malt  liquors  of  the  nature  of  beer.  They  con- 
tain about  2  per  cent,  of  alcohol,  by  volume,  and  much  nutritive 
extractive.  In  some  cases  they  are  made  bitter  with  hops. 
They  have  very  feeble  digestant  power  for  starch. 

Taka-diastase,  a  ferment  with  diastatic  properties,  is  obtained 
from  a  mold,  Aspergillus  oryzce,  which  grows  in  Japan  upon  the 
rice  plant. 

Papain  is  an  enzyme  obtained  from  the  juice  of  the  unripe 
fruit  of  Carica  papaya,  a  South  American  papaw  plant.  It  can 
digest  albumin  in  a  medium  that  is  alkaline,  neutral,  or  acid, 
but  acts  best  in  one  that  is  slightly  acid.  It  has  no  special 
indications. 

Ingluvin  is  the  dried  lining  membrane  of  the  chicken's  crop. 
Its  digestive  power  is  not  very  great.  It  has  been  given  in 
doses  of  5  grains  (0.3  gm.)  after  each  meal  in  the  nausea  and 
vomiting  of  pregnancy,  but  its  use  is  purely  empiric. 

Secretin,  owing  to  its  unstable  nature,  has  not  as  yet  come  into 
general  therapeutic  use. 

Hormonal  is  a  preparation  from  the  spleen  of  the  rabbit. 
It  is  said  to  contain  the  same  peristaltic  hormone  as  the  gastric 
mucous  membrane.  Reports  as  to  its  value  differ  widely,  but 
a  number  of  authorities  have  obtained  good  and  continued  action 
of  the  bowels  in  post-operative  tympanites  and  obstinate  chronic 
constipation.  It  tends  to  cause  headache  and  a  marked  fall 
in  blood-pressure,  and  anaphylaxis  has  occurred.  Rosenkranz 
reported  collapse  from  10  c.c.  intravenously;  Frischberg  reports 
collapse  from  20  c.c,  with  chill  and  a  temperature  of  105. 8°  F. 
From  the  intravenous  use,  Hoxie  obtained  good  results  in  two 
out  of  three  patients  with  chronic  constipation,  and  no  effect 
from  the  intramuscular  injection.  Dittler  and  Mohr  attribute 
the  peristalsis  to  the  fall  in  pressure,  and  question  the  presence  of 
a  hormone.  It  is  given  in  dose  of  15  to  40  c.c.  intravenously 
or  intramuscularly,  the  latter  being  painful.  For  intravenous 
use  it  is  marketed  pure,  and  for  intramuscular  use,  with  0.25  per 
cent,  of  beta-eucaine  chloride.  Zuelzer  claims  that  the  collapse 
was  due  to  albumose,  and  that  at  present  only  albumose-free 
hormonal  is  marketed. 


As  there  is  a  tendency  for  these  ferments  to  destroy  one 
another,  mixtures  of  digestive  ferments,  especially  those  which 


THE   INORGANIC   ACIDS  8 1 

act  in  different  media,  as  pepsin  and  pancreatin,  are  theoretically 
irrational.  Pepsin,  for  instance,  destroys  the  trypsin  of  pan- 
creatin, and  trypsin  destroys  pepsin  (Sollmann).  The  examina- 
tion by  the  chemists  of  the  American  Medical  Association  of 
several  such  proprietary  mixtures  has  shown  them  to  be  inert 
or  to  have  a  weak  action  of  the  ferment  that  happens  to  be  in 
excess. 

THE  INORGANIC  ACIDS 

The  inorganic  acids  in  common  use  for  their  acidity  are 
hydrochloric,  nitric,  phosphoric,  and  sulphuric.  Their  dose  is 
5  minims  (0.3  c.c.)  well  diluted.  Each  has  an  official  10  per  cent, 
dilution;  but,  as  shown  by  the  following  table,  the  strong  acids 
are  not  10  times  as  strong  as  the  diluted  acids.  The  relative 
percentage  strengths  are  as  follows: 

Hydrochloric  acid .  .  .  .  j/.p  per  cent .  .  .  .Diluted  hydrochloric  acid .  ... 70  per  cent. 

Nitric  acid 68.0    "      "      .  .  .Diluted  nitric  acid 10    "     " 

Phosphoric  acid   85.0    "      "      .  .  .Diluted  phosphoric  acid 10    "     " 

Sulphuric  acid 92.5    "      "      . .  .Diluted  sulphuric  acid 10    "     " 

Aromatic  sulphuric  acid  (acidum  sulphuricum  aromaticum) 
is  a  10  per  cent,  solution  (by  volume)  of  sulphuric  acid  in  alcohol 
flavored  with  ginger  and  cinnamon. 

Nitrohydrochloric  acid  (acidum  nitrohydrochloricum)  is  made 
by  acting  on  82  parts  of  hydrochloric  acid  with  18  parts  of  nitric 
acid.  A  violent  reaction  takes  place,  the  acids  being  split  up  to 
form  nitrosyl  chlorides  and  chlorine.     The  reactions  are: 

HN03+3HC1=   N0C1+C12  +  2H20 
2HN03+6HC1  =  2N0C12+C12-|-4H20 

There  is  a  slight  excess  of  hydrochloric  acid  (Amy),  so  that 
nitrohydrochloric  acid  is  a  liquid  containing  free  hydrochloric 
acid,  free  chlorine,  and  nitrosyl  chlorides,  the  original  acids  having 
lost  their  identity.  It  is  a  corrosive  h'quid  with  an  unpleasant 
odor.  Diluted  nitrohydrochloric  acid  is  about  one-fourth  this 
strength.     It  does  not  keep. 

Action. — The  strong  acids  are  caustic,  destroying  the  cells  by 
the  absorption  of  water,  by  the  neutralization  of  alkali,  and  by 
other  destructive  chemic  changes.  Sulphuric  acid  chars  organic 
matter;  nitric  acid  turns  it  yellow.  The  diluted  acids  induce  a 
reflex  flow  of  saliva.  This  is  especially  rich  in  protein,  and 
serves  to  take  up  and  neutralize  the  acid.  In  the  stomach  they 
promote  the  flow  of  gastric  juice,  and  secondarily,  by  their 
influence  in  the  production  of  secretin,  promote  the  flow  of 
pancreatic  juice  and  bile. 
6 


82  PHARMACOLOGY  AND   THERAPEUTICS 

Toxicology. — When  a  strong  acid  is  swallowed,  it  causes  burn- 
ing and  corrosion  of  the  mouth,  throat,  esophagus,  and  stomach. 
The  most  corrosive  acids  are  nitric  and  sulphuric.  From  poison- 
ous amounts,  whether  diluted  or  not,  there  are  the  systemic  symp- 
toms of  acute  acidosis,  i.  e.,  dyspnea,  twitching,  convulsions, 
coma,  collapse,  and  death.  Ewing's  conclusions  from  the  experi- 
mental production  of  acute  acidosis  were:  It  is  possible  to  kill 
animals  by  injection  of  mineral  acids  or  even  of  organic  acids  in 
large  quantity,  and  such  animals  die  with  marked  reduction  in 
the  acid-neutralizing  properties  of  the  blood,  and  with  diminished 
carbon  dioxide  content  sufficient  to  explain  their  peculiar  dyspnea. 
The  urine  shows  marked  excess  of  ammonia  nitrogen  and  diminu- 
tion of  urea.  The  autopsy  findings  indicate  death  from  asphyxia. 
It  must  be  remembered  that  the  basicity  of  the  blood,  that  is, 
its  acid  neutralizing  power,  depends  not  alone  on  alkalies,  but 
also  largely  upon  protein,  urea,  and  other  nitrogenous  sub- 
stances (Ewing). 

Treatment. —  (a)  Local. — The  local  antidotes  in  the  ali- 
mentary tract  are  mild  alkalies,  such  as  soap,  lime,  and  magnesia. 
The  carbonated  alkalies,  such  as  chalk,  sodium  carbonate,  and 
sodium  bicarbonate,  must  be  used  with  great  caution,  if  at  all, 
for  with  the  acid  they  liberate  C02  gas,  and  this  may  result  in 
collapse  from  sudden  distention  of  the  stomach  or  rupture  of  the 
corroded  stomach- wall. 

(b)  Systemic. — To  combat  the  acidosis  half  an  ounce  of  sodium 
bicarbonate  dissolved  in  one  or  two  pints  of  hot  water  may  be 
given  slowly  by  rectum;  or  a  3.5  per  cent,  solution  of  sodium 
carbonate  may  be  administered  intravenously  (von  Noorden). 
In  chronic  acidosis  the  administration  of  proteins,  and  especially 
of  amino-acids  to  furnish  NH3,  the  natural  antidote  to  acid 
excess,  has  been  tried,  without  great  success.  The  administra- 
tion of  carbohydrates  has  been  of  more  value. 

Therapeutics. — Nitric  acid  is  occasionally  used  for  the  destruc- 
tion of  warts  or  small  nevi.  It  causes  pain,  and  often  leaves  a 
scar.  Its  stains  of  the  skin  are  yellow  and  indelible.  Being  a 
powerful  coagulant  of  albumin,  it  is  not  an  aid  to  digestion. 

Hydrochloric  acid  is  sometimes  employed  when  the  natural 
acid  of  the  gastric  juice  is  deficient  or  absent.  It  is  then  given 
in  amounts  of  5-10  minims  (0.3-0.7  c.c.)  in  a  glass  of  water  to  be 
drunk  during  the  meal.  This  may  be  repeated  in  half  or  one  hour. 
It  is  believed  by  some  that  the  acid  in  these  cases  serves  as  an 
antiseptic  to  prevent  the  development  of  gas-forming  organisms 
in  the  stomach  and  the  passage  of  putrefactive  bacteria  into  the 
intestines.     There  is  some  good  evidence  against   this  belief. 


THE    ORGANIC   ACIDS  83 

The  diluted  hydrochloric  acid,  it  will  be  noted,  is  about  one-third 
the  strength. 

Oxyntin  and  acidol  are  albuminous  compounds  of  hydrochloric 
acid  recently  introduced  for  the  administration  of  hydrochloric 
acid  in  solid  form.  They  are  strongly  acid  to  the  taste.  It  is 
claimed  that  10  grains  (0.7  gm.)  of  oxyntin  represent  5  minims 
(0.3  c.c),  and  10  grains  of  acidol  represent  7.5  minims  (0.5  c.c.) 
of  hydrochloric  acid  (U.S. P.). 

Dilute  nitric,  nitrohydrochloric,  and  phosphoric  acids  are 
sometimes  employed  for  the  same  purpose  as  hydrochloric. 
There  is  no  reason  for  preferring  them  to  hydrochloric,  which  is 
the  natural  acid  of  the  gastric  juice;  and,  as  noted  above,  nitro- 
hydrochloric is  an  irritant  chlorine  preparation. 

Sulphuric  acid,  both  internally,  in  dose  of  5  minims  (0.3  c.c), 
and  externally,  has  been  employed  for  the  night-sweats  of  tu- 
berculosis. In  the  author's  experience  it  is  of  no  value.  It  was 
formerly  the  custom  to  employ  diluted  sulphuric  acid  or  aromatic 
sulphuric  acid  to  bring  quinine  sulphate  into  solution,  but  since 
it  does  so  by  changing  the  insoluble  sulphate  to  the  soluble  bisul- 
phate,  it  would  be  better  to  use  the  bisulphate  at  the  outset  and 
avoid  employing  an  arbitrary  amount  of  acid. 

THE  ORGANIC  ACIDS 

Citric  acid  (acidum  citricum,  H3C6H5O7)  occurs  in  large 
quantities  in  fruits  of  the  citrus  family,  the  lemon,  orange,  lime, 
and  grape-fruit;  and  in  milk  to  the  extent  of  0.1-0.25  Per  cent. 

Tartaric  acid  (acidum  tartaricum,  H0C4H4O6)  occurs  in  grapes. 

They  are  both  crystalline  solids,  readily  soluble  in  water.  In 
the  duodenum  they  form  sodium  citrate  and  tartrate.  These  salts 
and  the  acids  are  not  readily  absorbed,  and  have  a  laxative  effect 
in  the  intestine;  but  when  absorbed,  they  are  changed  to  car- 
bonate in  the  blood,  and  so  serve  as  systemic  alkalinizers,  though 
themselves  of  acid  reaction.  Lemonade  and  Imperial  drink  are 
refreshing  drinks  in  fever.  The  latter  is  made  by  dissolving  y2 
ounce  (15  gm.)  of  potassium  bitartrate  (cream  of  tartar)  in  3 
pints  (1.  liters)  of  boiling  water,  and  adding  4  ounces  (120  gm.) 
of  sugar  and  y2  ounce  (15  gm.)  of  fresh  lemon-peel.  In  the  duo- 
denum potassium  bitartrate,  which  has  an  acid  reaction,  forms 
Rochelle  salt  (potassium  and  sodium  tartrate). 

When  a  weak  solution  of  a  soluble  citrate  is  mixed  with  or 
injected  into  the  blood,  it  takes  up  calcium  and  has  a  retarding 
influence  upon  the  clotting  of  the  blood.  Because  of  this  action, 
citric  acid  in  dose  of  10  grains  (0.7  gm.)  three  times  a  day  has 
been  recommended  in  the  late  stages  of  typhoid  fever  to  prevent 


84  PHARMACOLOGY  AND  THERAPEUTICS 

thrombosis.  But  Rudolf  and  Cole  (191 1)  have  determined  that 
citric  acid  administered  by  mouth  does  not  essentially  influence 
the  time  of  coagulation  of  the  blood  either  in  typhoid  fever  or  in 
other  conditions;  and  Addis  (1909)  has  shown  that  in  the 
amounts  which  it  is  possible  to  administer  therapeutically  the 
drug  does  not  affect  coagulability.  Weiss  says  that  it  requires 
at  least  5  or  6  grams  a  day  to  have  any  effect.  Citric  acid  also, 
according  to  Hofmeister,  lessens  the  viscosity  of  the  blood  by 
converting  sols  into  gels. 

Formic  acid  (acidum  formicum,  HCOOH)  has  been  employed 
locally  and  internally  in  rheumatism.  It  is  present  in  the  secre- 
tion of  the  sting  of  the  bee,  and  has  been  employed  by  allowing 
bees  to  sting  the  involved  part. 

Acetic  acid  (acidum  aceticum,  CH3COOH)  is  the  essential 
ingredient  of  vinegar.  The  Pharmacopoeia  recognizes  glacial 
acetic  acid  of  99  per  cent,  strength,  which  is  used  for  the  removal 
of  warts;  acetic  acid,  of  36  per  cent,  strength;  and  diluted  acetic 
acid,  of  6  per  cent,  strength.  The  last  is  of  the  strength  of  good 
vinegar.  A  2  per  cent,  solution  is  also  employed  as  an  intra- 
uterine hemostatic  in  postpartum  hemorrhage.  Trichloracetic 
acid,  CCI3COOH,  is  strongly  caustic,  and  is  employed  in  the 
removal  of  warts,  small  nevi,  and  hypertrophied  tissue,  such  as 
occurs  in  the  nose.  The  acetates  are  freely  soluble  in  water, 
are  readily  absorbed,  and  by  changing  to  carbonate  act  as  agents 
to  alkalinize  the  blood.  They  are  diuretic,  and  their  intravenous 
administration  is  followed  by  a  fall  in  arterial  pressure,  and  dila- 
tation of  the  kidney  arterioles. 

Lactic  acid  (acidum  lacticum,  C3H603),  obtained  by  fermenta- 
tion from  sugar-of-milk,  finds  its  chief  use  in  10  to  50  per  cent, 
solution  in  glycerin  as  an  application  to  tuberculous  ulcers  of  the 
throat. 

Recently,  on  the  theory  that  putrefactive  germs  in  the  in- 
testines are  inhibited  by  lactic-acid  germs  and  their  products, 
the  lactic-acid  drinks  have  come  into  extensive  use  both  by  physi- 
cians and  the  laity.  Such  drinks  are:  zoolak,  fermillac,  kumyss, 
sour  milk,  buttermilk,  etc.  Special  strains  of  lactic-acid  bacteria 
are  also  sold  to  be  used  in  making  sour  milk,  or  to  be  swallowed 
in  the  form  of  capsules,  tablets,  or  liquids.  Whether  or  not  this 
form  of  medication  has  any  real  value  is  still  a  moot  question, 
some  more  recent  researches  indicating  little  if  any  use  for  the 
drinks  except  for  their  nutritive  constituents.  Lactic  acid  drinks 
are  prone  to  induce  attacks  of  gastric  hyperacidity,  and  to  bring 
on  rheumatic  manifestations  in  those  subject  to  rheumatism.  A 
recent  claim  that  they  are  of  value  in  diabetes  requires  extensive 
clinical  testing. 


FRUIT   ACIDS  85 

Oxalic  acid  (H2C204)  has  no  use  in  therapeutics,  but  is  of 
interest  because  of  the  frequency  of  its  poisoning.  This  usually 
occurs  from  the  drinking  of  solutions  used  in  the  kitchen  for 
brightening  copper  boilers.  The  crystals  resemble  somewhat 
those  of  Epsom  salts.  There  are — (1)  Severe  irritation  of  the 
gastro-intestinal  tract,  with  vomiting,  diarrhea,  and  cramps,  and 
(2)  nervous  manifestations,  from  twitching  of  the  muscles  to 
complete  tetany  (continuous  cramps  of  voluntary  muscles),  and 
convulsions,  coma,  and  death.  When  death  does  not  ensue, 
there  may  be  a  remote  local  effect  upon  the  kidneys  resulting  in 
nephritis.  The  systemic  symptoms  are  those  of  acidosis,  or  of 
the  removal  from  the  system  of  calcium,  for  which  oxalic  acid 
has  a  great  affinity. 

The  chemic  antidote  for  the  stomach  is  a  calcium  salt,  such  as 
lime  or  the  chloride  or  lactate,  to  form  the  insoluble  and  non- 
corrosive  calcium  oxalate.  Even  wall-plaster  may  serve  if  there 
is  no  lime  at  hand.  For  the  systemic  symptoms  the  need  is  to 
alkalinize  and  to  supply  calcium;  therefore  a  pint  (500  c.c.) 
of  a  solution  of  0.25  per  cent,  of  calcium  chloride  with  1  per  cent. 
of  sodium  bicarbonate  may  be  administered  intravenously. 
Copious  drafts  of  water  should  be  given  by  mouth  to  promote  the 
elimination  of  oxalate  by  the  kidneys. 

FRUIT  ACIDS 

The  organic  acids  in  fruits  are  chiefly  acetic,  malic,  citric, 
tartaric,  oxalic,  and  in  some  instances  salicylic  and  boric.  Malic 
acid  and  malates  occur  in  apples,  pears,  currants,  blackberries, 
raspberries,  quince,  pineapple,  cherries,  and  rhubarb.  Citric 
acid  and  citrates  occur  in  large  quantities  in  lemons,  oranges, 
grape-fruit,  and  lime,  and  slightly  in  quince,  gooseberry,  straw- 
berry, raspberry,  currant,  and  cranberry.  Tartaric  acid  occurs 
in  grapes. 

According  to  Blyth,  the  percentage  of  free  acid  present  in 
the  various  fruits  is  as  follows:  Pear,  0.2;  grape,  0.79;  apple, 
0.84;  plum,  0.85;  cherry,  0.91;  peach,  0.92;  strawberry,  0.93; 
apricot,  1.16;  blackberry,  1.19;  raspberry,  1.38;  gooseberry, 
1.42;  prune,  1.5;  mulberry,  1.86;  currant,  2.15.  Lemon-juice 
contains  about  6  per  cent,  of  citric  acid. 

It  must  be  remembered  that  the  relative  acidity  cannot  be 
determined  by  taste,  as  the  proportions  of  sugar  differ  in  the 
different  fruits.  For  example,  while  strawberries,  currants, 
gooseberries,  huckleberries,  apples,  pears,  and  prunes  contain 
between  5  and  8  per  cent,  of  sugar,  raspberries,  blackberries, 
apricots,  plums,  and  peaches  contain  less  than  5  per  cent.; 
cherries  contain  10  per  cent.,  and  grapes,  from  15  to  24  per  cent. 


86  PHARMACOLOGY  AND  THERAPEUTICS 

(Blyth,   Fresenius).     The  amount  of  sugar  also  regularly  in- 
creases with  the  ripeness  of  the  fruit. 

ANTACIDS 

The  therapeutically  employed  antacids  are  certain  salts  of 
the  alkalies,  potassium,  sodium,  lithium,  and  ammonium,  and 
certain  salts  of  the  alkaline  earths,  magnesium  and  calcium.  Of 
the  metals  mentioned,  K,  Na,  and  Li  are  ions  of  ready  absorba- 
bility from  the  alimentary  tract,  while  Mg  and  Ca  are  absorbed 
with  comparative  difficulty.  Hence  after  a  local  action  in  the 
stomach  the  salts  of  the  former  for  the  most  part  manifest  a 
systemic  action,  while  those  of  the  latter  have  a  special  intestinal 
activity,  magnesium  salts  being  laxative  and  those  of  calcium 
constipating. 

The  antacids  are  of  two  types: 
I.  Those  of  alkaline  reaction. 

II.  Those  not  of  alkaline  reaction. 

THE  ANTACIDS   OF  ALKALINE  REACTION 

These  can  neutralize  acids,  and  they  have  both  a  local  and  a 
systemic  effect  as  alkalinizers.  They  are  chiefly  oxides,  hydrox- 
ides, and  carbonates,  and  may  be  differentiated  into  two  groups, 
the  caustic  alkalies  and  the  mild  alkalies. 

(a)  The  caustic  alkalies  are  the  hydroxides  of  potassium 
(KOH)  and  sodium  (NaOH)  and  the  oxide  of  calcium  (CaO, 
lime;  Lat.,  calx).  They  destroy  tissue  by  abstracting  water, 
by  dissolving  albumin,  and  by  saponifying  fats.  Even  in  dilute 
solution  the  potassium  and  sodium  hydroxides  are  more  pene- 
trating and  more  irritant  than  the  other  alkalies.  The  official 
solutions  of  potassium  hydroxide  and  sodium  hydroxide  are  of 
about  5  per  cent,  strength.     They  are  strongly  caustic. 

(b)  The  milder  alkalies  are  the  carbonates  and  bicarbonates 
of  potassium,  sodium,  and  lithium,  and  the  carbonates  and  hy- 
droxides of  magnesium  and  calcium.  The  salts  of  potassium, 
sodium,  and  lithium  are  preferred  for  simple  alkalinity,  the  mag- 
nesium salts  when  there  is  constipation,  and  the  calcium  salts 
when  there  is  diarrhea. 

POTASSIUM,  SODIUM,  AND  LITHIUM 

The  official  mild  alkaline  salts  of  these  ions  are: 

Potassium  bicarbonate  (KHC03),  soluble  in  3  parts  of  water. 

Potassium  carbonate  (K2CO3),  "salts  of  tartar,"  soluble  in 
0.91  part  of  water. 

Sodium  bicarbonate  (NaHC03),  "baking  soda,"  soluble  in  12 
parts  of  water. 


POTASSIUM,    SODIUM,    AND   LITHIUM  87 

Monohydrated  sodium  carbonate  (Na2C03+H20),  dried  so- 
dium carbonate,  soluble  in  3  parts  of  water.  Washing-soda 
is  crystalline  sodium  carbonate  (Na2C03+ioH20).  Both  are 
rather  irritating  to  the  tissues  and  are  not  used  internally. 

Lithium  carbonate  (Li2C03),  soluble  in  75  parts  of  water. 

All  these  salts  are  insoluble  in  alcohol.  In  aqueous  solution 
the  bicarbonates  slowly  change  to  carbonate  by  loss  of  carbon 
dioxide.  When  heated,  they  change  more  rapidly,  hence  any 
liquid  containing  sodium  or  any  other  bicarbonate  should  not  be 
boiled. 

Potassium. — Since  potassium  chloride  in  the  blood,  in 
amounts  above  1  :  10,000,  slows  and  weakens  the  heart  and 
retards  the  activity  of  other  muscles,  the  potassium  ion  has  been 
considered  a  muscle  depressant.  But  in  our  food  we  ingest  at 
least  yi  ounce  (15  gm.)  of  potassium  salts  daily,  and  if  the  diet 
is  a  purely  vegetable  one,  sometimes  as  much  as  3  ounces  (90 
gm.)  daily.  So  that  potassium  salts,  as  administered  in  thera- 
peutics by  mouth,  may  be  considered  non-depressant  and  inert, 
so  far  as  their  potassium  is  concerned,  at  least  in  any  but  enor- 
mous doses.  Dixon  says  that  we  do  not  get  their  specific  action 
because  they  are  excreted  so  rapidly. 

Lithium. — Since  the  lithium  salts  of  uric  acid  are  more 
soluble  than  the  corresponding  sodium  salts,  lithium  has  been 
favored  as  the  alkali  in  gout  and  the  uric-acid  diathesis.  But 
the  quadriurate,  which  seems  to  be  the  responsible  irritant  in 
attacks  of  gout,  is  not  rendered  soluble  by  any  lithium  salt  except 
in  concentrated  solution;  and  is  not  prevented  by  lithium,  so 
far  as  known,  from  forming  in  gouty  subjects.  Hence  lithium 
has  no  preference  over  potassium  and  sodium,  even  in  gout  and 
the  uric-acid  diathesis.  As  a  matter  of  fact,  alkalies  are  not  now 
considered  good  remedies  in  gout.  The  lithia  waters  on  the 
market  are  chiefly  remarkable  for  the  minuteness  of  the  amount 
of  lithia  present,  several  gallons,  as  a  rule,  containing  not  more 
than  a  single  therapeutic  dose. 

Cleaveland  (19 13)  reports  lithium  poisoning  in  himself  on  two 
occasions.  The  first  time  he  took  120  grains  (8  gm.)  of  lithium 
chloride  in  twenty-eight  hours.  The  symptoms  began  after  the 
first  dose  of  2  grams.  There  were  fulness  in  the  head,  dizziness, 
ringing  in  the  ears,  and  blurring  of  the  vision,  followed  by  tremors 
and  marked  prostration.  The  second  time,  several  months 
later,  he  took  60  grains  (4  gm.)  and  the  symptoms  were  repeated. 
He  felt  as  if  he  had  taken  a  large  dose  of  quinine.  There  were  no 
gastro-intestinal  symptoms.  C.  A.  Good  (1903),  in  experiments 
on  cats  and  dogs,  found  that  60  mg.  per  kilo  daily  invariably 
caused  death  sooner  or  later  from  gastro-enteritis. 


88  PHARMACOLOGY  AND  THERAPEUTICS 

Sodium. — Even  sodium  chloride  is  poisonous  under  certain 
circumstances,  and  Jacques  Loeb  believes  that  the  function  of 
potassium  and  calcium  salts  in  the  blood  and  in  sea-water  is  to  pre- 
vent penetration  of  cells  by  too  much  sodium  chloride.  A  number 
of  cases  of  poisoning  from  concentrated  saline  used  intravenously 
or  by  rectum  instead  of  normal  saline  have  been  reported,  the 
symptoms  being  nausea,  vomiting,  diarrhea,  maniacal  delirium 
or  coma,  fever  up  to  1040  F.,  collapse,  and  death.  In  a  fatal  case 
of  a  woman  given  1920  grains  (64  gm.)  by  hypodermoclysis  in 
mistake  for  normal  saline,  Combs  noted  crenation  of  the  red  cells 
in  the  fresh  blood.  Barlow  reports  that  the  drinking  of  a  pint 
or  more  of  the  saturated  solution  is  a  common  method  of  com- 
mitting suicide  in  Chekiang  province,  China.  Campbell  cites 
a  case  of  death  in  a  boy  of  five  who  was  given  a  pound,  instead 
of  a  tablespoonful,  of  salt  in  a  quart  of  water  as  an  enema  for 
worms. 

From  normal  saline  in  "salt  retention"  cases  there  may  be 
edema  of  the  lungs,  general  edema,  and  vomiting  of  fluid  rich 
in  chlorides.  (See  Saline  Infusion,  under  Measures  for  In- 
creasing the  Volume  of  the  Blood.)  Bryant  reported  the  case 
of  a  physician  who  developed  serious  edema  of  the  legs  after 
eating  very  large  quantities  of  salt  with  his  meals  for  several 
weeks.     Stoppage  of  the  habit  resulted  in  cure. 

Sodium  chloride  should  not  be  administered  as  an  infusion 
or  rectal  injection  in  parenchymatous  nephritis,  eclampsia,  or 
any  condition  with  edema. 

Sodium  Bicarbonate  (Sodii  Bicarbonas). — For  alkalinity, 
the  favored  salt  is  sodium  bicarbonate  (NaHCOs).  This  salt 
is  extensively  employed  both  externally  and  internally.  Five 
grains  (0.3  gm.)  will  neutralize  6.2  minims  (0.4  c.c.)  of  hydro- 
chloric acid  (U.S. P.),  about  22  minims  (1.5  c.c.)  of  diluted 
hydrochloric  acid,  and  i}4  ounces  (45  c.c.)  of  gastric  juice  of 
0.03  per  cent,  strength.  The  alkalinity  of  its  solution  increases 
on  standing,  owing  to  the  loss  of  carbon  dioxide.  Externally,  in 
solution,  it  is  a  solvent  for  dried  exudates,  such  as  the  crusts  in 
seborrheic  eczema;  and  either  in  solution  or  paste  is  a  soothing 
application  in  erythema,  urticaria,  itching,  insect-bites,  and  burns. 
It  is  not  caustic.  To  mucous  membranes  its  solutions  are  soothing, 
and  they  act  as  solvents  for  thick  mucus. 

Alimentary  Tract. — Sodium  bicarbonate  neutralizes  acids 
and  dissolves  mucus.  According  to  Pawlow  (1897),  it  tends  to 
inhibit  salivary,  gastric,  and  pancreatic  secretion.  But  in 
Pawlow's  laboratory,  Sawitch  and  Zeliony  (1913)  have  demon- 
strated that  when  it  is  applied  to  the  pyloric  mucosa  it  causes 
acid  gastric  juice  to  be  secreted  by  the  stomach  in  general. 


ANTACIDS 


89 


This  last  finding  points  to  the  action  of  regurgitated  bile,  but  its 
significance  in  therapeutics  is  not  apparent  at  present. 

The  effect  of  an  alkali  in  the  stomach  will  vary  greatly  ac- 
cording to  the  nature  of  the  stomach-contents  at  the  time  of 
its  administration.  In  the  resting  period,  sodium  bicarbonate 
merely  dissolves  mucus  and  is  absorbed  as  bicarbonate  into  the 
blood,  to  increase  its  alkalinity  directly.  In  the  digestive  period 
it  reduces  the  secretion  of  gastric  juice,  neutralizes  a  portion  of 
the  hydrochloric  acid,  liberates  the  carminative  carbon  dioxide 
gas,  and  is  absorbed  as  sodium  chloride.  In  cases  of  fermentation 
or  "sour  stomach"  it  may  neutralize  the  organic  acids,  and  so 
result  in  the  opening  of  a  spasmodically  closed  pylorus;  while 
at  the  same  time  its  CO2  acts  to  overcome  flatulency. 

The  time  of  administration  must,  therefore,  be  chosen  with 
a  definite  purpose.  Usually  for  hyperchlorhydria  one  hour  or 
two  hours  after  meals  will  be  the  period  of  harmful  excess  of  acid. 
In  continuous  hyperacidity  and  in  fermentative  conditions  a 
dose  an  hour  before  meals  will  tend  to  prepare  the  stomach  for 
the  next  meal ;  or  sometimes  a  dose  will  be  necessary  immediately 
after  eating,  because  of  abnormal  acid  or  gas  having  been  present 
at  the  commencement  of  the  meal.  A  dose  at  bedtime  tends  to 
check  the  early  morning  acidity,  or  a  dose  on  arising  cleans  the 
stomach  of  acid  and  mucus  before  breakfast.  In  duodenal 
ulcer  it  may  be  needed  when  the  "empty  pain"  comes  on.  In 
alcoholic  gastritis  it  may  be  used  in  solution  for  lavage  to  remove 
excessive  thick  mucus. 

In  acidosis,  if  the  bicarbonate  is  wanted  as  a  systemic  alka- 
linizer,  it  is  preferably  given  shortly  before  meals,  when  the 
stomach  is  not  acid ;  though  it  has  an  indirect  alkalinizing  effect 
upon  the  blood  and  urine,  no  matter  at  what  time  it  is  given. 
Howell  states  that  a  less  alkaline  state  of  the  blood  causes  re- 
laxation of  the  blood-vessels,  while  an  increase  in  the  alkalinity 
improves  their  tone.  But  rapid  excretion  makes  it  difficult  to 
produce  more  than  temporary  changes  in  the  alkalescence  of 
the  blood. 

In  severe  conditions  of  acidosis,  as  in  diabetic  coma  or  de- 
layed chloroform  poisoning,  enormous  doses — up  to  ^2  ounce  (15 
gm.) — have  been  given  by  mouth;  and  by  rectum,  by  the  con- 
tinuous drop  method,  as  much  as  50  gm.  per  day  in  3  per  cent, 
solution.  These  amounts,  with  sodium  carbonate  intravenously 
in  3.5  to  4  per  cent,  solution,  give  only  occasional  good  results 
(von  Noorden) ;  and  the  reason  for  this  may  be  that  in  diabetes 
there  is  no  change  in  the  alkalinity  of  the  blood  as  judged  by 
the  hydroxy  1  ions,  though  in  acidosis  from  mineral  acids  the 
blood  is  acid  (Folin). 


90  PHARMACOLOGY  AND  THERAPEUTICS 

In  rheumatism  it  is  given  until  the  urine  is  alkaline.  In 
gout  alkalies  are  useless  and  perhaps  harmful  (von  Noorden). 
Fauvel  states  that  as  much  as  i,K  ounces  (6  gm.)  a  day  has  no 
effect  on  the  excretion  of  xanthines  or  uric  acid.  Following 
Fischer's  recent  theory  of  acid  as  a  cause  of  nephritis,  it  has  been 
employed  in  this  disease,  but  neither  the  theory  nor  the  treat- 
ment seems  satisfactory.  By  increasing  the  salts  of  the  blood 
it  is  diuretic.     In  some  cases  it  is  distinctly  laxative. 

The  other  carbonated  alkalies  have  similar  actions,  but  are 
less  employed.  Folin  suggests  that  a  mixture  of  sodium,  potas- 
sium, calcium,  and  magnesium  salts  would  be  better  than  sodium 
bicarbonate  alone. 

MAGNESIUM 

The  magnesium  antacids  are  the  oxide,  the  hydroxide,  and 
the  carbonate.  Perhydrol  (unofficial)  is  the  magnesium  per- 
oxide. The  magnesium  oxide  (magnesii  oxidum)  of  the  Pharma- 
copoeia, or  burnt  magnesia,  is  a  very  light,  odorless  white  powder, 
which,  when  exposed  to  air,  slowly  changes  to  carbonate,  One 
part  of  it,  on  being  mixed  with  15  parts  of  water  and  allowed  to 
stand  half  an  hour,  hydrates  and  forms  a  gelatinous  mass.  The 
heavy  oxide  (magnesii  oxidum  ponderosum)  is  $lA  times  as 
heavy  and  does  not  readily  hydrate.  Magnesium  hydroxide 
comes  in  the  form  of  a  thick  white  liquid  or  magma  (magma 
magnesiae,  N.  F.),  commonly  called  "milk  of  magnesia."  This 
is  formed  by  precipitating  a  solution  of  magnesium  sulphate 
with  sodium  hydroxide,  which  leaves  the  magnesium  hydroxide 
suspended  in  the  water  in  a  line  state  of  subdivision.  It  contains 
about  3  grains  (0.2  gm.)  of  magnesium  hydroxide  in  each  dram 
(4  ex.).  Magnesium  carbonate  (magnesii  carbonas) ,  (MgC03)4. 
Mg(OH)2-r-5H20,  is  a  white,  insoluble  powder,  capable  of 
neutralizing  acids  with  the  liberation  of  carbon  dioxide  gas. 

These  magnesium  salts  are  all  very  weak  alkalies  without 
any  caustic  action,  but  they  have  considerable  combining  power 
for  acid.  The  oxide  in  the  hydrated  gelatinous  form  will  neutral- 
ize \]/2  times  its  weight  of  hydrochloric  acid  (U.S.  P.).  They 
all  act  as  cathartics,  and  will  be  considered  further  under  that 
heading.  Following  a  communication  of  Meltzer  and  Lucus 
(1907)  on  magnesium  poisoning,  it  has  been  ascertained  that  the 
magnesium  ion  exerts  a  curare-like  action  on  striped  muscle, 
and  causes  death  by  paralysis  of  respiration.  (See  Magnesium 
Sulphate  under  Cathartics  and  Local  Anesthetics.) 

CALCIUM 
Preparations. — The  mildly  alkaline  salts  are  the  carbonate 
and   the  hydroxide.     The   carbonates   are  insoluble  in  water. 


CALCIUM  91 

The  salts  for  systemic  action  are  the  chloride  and  the  lactate, 
both  soluble  in  water,  the  former  being  deliquescent.  The  car- 
bonate (CaC03)  comes  in  two  forms — " prepared  chalk"  (creta  prae- 
parata)  and  "precipitated  chalk"  (calcii  carbonas  praecipitatus) . 
The  latter  is  in  the  form  of  a  heavy  fine  powder,  may  be  obtained 
pure,  and  is  much  used  in  tooth-powders.  The  former  is  pre- 
pared from  native  chalk  and  contains  impurities,  but  because  of 
a  cohesive  tendency  has  been  much  used  in  liquids  for  internal 
use.  It  comes  in  heavy,  cone-shaped  lumps,  and  is  often  called 
"drop-chalk,"  from  its  method  of  manufacture.  It  constitutes 
30  per  cent,  of  compound  chalk  powder  (pulvis  cretae  compositus) ; 
and  this  is  kept  on  hand  for  the  fresh  manufacture  of  chalk  mixture 
(mistura  cretae),  dose,  2  drams  (8c.c).  This  mixture  unfortunately 
contains  the  fermentable  substances,  sugar  and  acacia,  and  does 
not  keep  well. 

The  hydroxide  is  employed  in  the  form  of  a  saturated  solution, 
known  as  lime-water  (liquor  calcis).  Lime-water  is  a  very  weak 
preparation,  containing  only  0.14  per  cent,  of  calcium  hydroxide, 
i.  e.,  about  11  grains  to  a  pint.  It  is  precipitated  by  heat.  To 
neutralize  1  minim  of  hydrochloric  acid,  ]/2  ounce  (15  c.c.)  is 
required.  On  exposure  to  air  it  takes  up  carbon  dioxide  and 
forms  calcium  carbonate,  which  precipitates.  Hence  lime-water 
tends  to  deteriorate,  and  samples  sometimes  contain  almost  no 
calcium  hydroxide.  Before  making  lime-water  the  slaked  lime 
should  always  be  washed  thoroughly,  to  remove  soluble  impuri- 
ties, as  directed  in  the  Pharmacopoeia. 

The  syrup  of  lime  (syrupus  calcis),  dose,  30  minims  (2  c.c), 
and  the  syrup  of  the  lacto phosphate  (syrupus  calcii  lactophos- 
phatis),  dose,  2  drams  (8  c.c),  are  official. 

Action. — The  relation  of  calcium  to  the  body  metabolism 
is  one  that  is  at  the  present  time  undergoing  much  study.  The 
body  obtains  its  supply  of  calcium  chiefly  from  drinking-water, 
eggs,  milk,  and  vegetable  foods,  and  slightly  from  animal  flesh. 
The  absorption  of  calcium  is  not  very  ready,  though  it  is  favored 
by  the  acid  of  the  gastric  juice.  From  60  to  80  per  cent,  of  the 
calcium  taken  by  mouth  passes  out  with  the  feces  (von  Noorden) , 
part  of  it  having  been  unabsorbed,  and  part  of  it  absorbed  and 
reexcreted.  After  a  hypodermatic  of  a  calcium  salt  it  quickly 
appears  in  the  colon.  In  the  urine  the  ordinary  daily  output 
is  from  0.1  to  0.5  gm.  per  day;  but  according  to  Beneker,  in 
sickness  and  all  conditions  of  debility,  and  in  starvation,  much 
more  than  usual  of  the  calcium  and  magnesium  phosphates  may 
appear  in  the  urine,  and  sometimes  enormous  quantities  (2  to 
4  gm.  a  day).  When  Soborow  gave  8  to  10  gm.  of  chalk  per  day, 
the  calcium  of  the  urine  rose  to  0.7-0.98  gm.     Hoppe-Seyler  says 


92  PHARMACOLOGY  AND   THERAPEUTICS 

this  excretion  is  favored  by  rest  in  bed,  the  bones  slowly  atrophy- 
ing and  giving  off  lime  salts.  Acid  conditions  favor  excretion 
by  the  kidneys  rather  than  by  the  colon,  hence  in  acidosis  from 
diabetes,  and  when  there  is  much  acid  in  the  food,  the  urinary 
output  of  calcium  rises  to  a  high  figure.  It  is  believed  that  the 
bones  may  contribute  extra  calcium  in  these  cases. 

Loeb  found  that  calcium  salts  can  stop  contact  irritability 
of  muscle  and  the  hypersensitiveness  of  the  nervous  system 
induced  by  various  salts;  as  a  consequence,  they  tend  to  check 
peristalsis  and  to  lessen  intestinal  secretion.  They  increase  the 
rapidity  of  action  of  the  coagulating  enzymes,  especially  of  the 
blood  and  milk.  They  antagonize  the  action  of  potassium  salts 
on  the  heart.  Loeb  has  recently  suggested  that  the  calcium  in 
the  blood  is  for  the  protection  of  the  cells  from  acids  and  sodium, 
the  potassium  and  calcium  making  a  relative  impermeability 
of  the  external  portion  of  the  protoplasm  of  the  cells.  The  lack 
of  sufficient  calcium  results  in  muscular  twitching,  and  it  is  be- 
lieved may  be  a  cause  of  tetany.  Loeb  noted  that  the  injection 
into  the  animal  body  of  a  salt  capable  of  precipitating  calcium, 
e.  g.,  the  oxalate  or  citrate  of  sodium,  results  in  muscular  twitching. 

Tetany  has  frequently  followed  removal  of  the  parathyroid 
glands,  and  both  in  tetany  and  after  parathyroidectomy  the 
calcium  content  of  the  brain  and  blood  has  been  found  diminished 
(Quest  and  MacCallum  and  Voegtlin).  It  has  also  been  shown 
by  the  last  two  investigators  that  the  nervous  manifestations 
following  parathyroidectomy  may  be  checked  by  the  administra- 
tion of  calcium  salts.  They  suggest  that  the  absence  of  the 
parathyroids  causes  an  "impoverishment  of  the  tissues  with 
respect  to  calcium,  and  the  consequent  development  of  a  hyper- 
excitability  of  the  nervous  system,  and  tetany."  Marine  and 
Lenhart  found  that  5  c.c.  of  a  5  per  cent,  solution  of  CaCl>  re- 
sulted in  the  recovery  of  a  dog  from  tetany  which  came  on  after 
a  thyroid  operation. 

It  is  well  known  that  infantile  tetany  usually  appears  in  those 
with  rickets.  Erdheim  (191 1)  reports  that  extirpation  of  the 
parathyroid  glands  of  white  rats  resulted  in  the  failure  of  full 
calcification  of  dentine  and  enamel  in  the  growing  teeth;  but 
that  on  transplanting  parathyroid  glands,  the  dentine  and  enamel 
layers  became  fully  calcified.  Erdheim  and  Canal  showed  fur- 
ther that  after  removal  of  the  parathyroids  callus  formation  is 
retarded.  These  facts  and  a  number  of  reported  cases  of  human 
tetany  relieved  by  calcium  lead  one  to  think  that  calcium- 
starvation,  or  disturbance  of  calcium  metabolism  through  failure 
of  the  parathyroids,  is  an  important  cause  of  tetany,  and  suggest 
the  intravenous  use  of  calcium  salts  in  this  disease  (Meltzer). 


CALCIUM 


93 


Coagulation  of  the  Blood. — It  is  an  old  observation  that 
calcium  salts  added  to  the  blood  outside  of  the  body,  or  intra- 
venously, increase  its  coagulability  and  lessen  its  coagulation 
time.  But  it  is  still  a  question  whether  calcium  salts  admin- 
istered by  mouth  have  such  an  effect.  Wright  and  Paramore 
(1905)  found  a  distinct  difference  within  an  hour  or  less;  but 
Rudolf  and  Cole  (191 1),  after  a  very  careful  series  of  studies, 
have  come  to  the  conclusion  that  "the  free  exhibition  of  calcium 
lactate  by  mouth  has  no  appreciable  effect  upon  the  coagulation 
of  the  blood";  and  Van  Lier  (191 2),  after  taking  the  coagulation 
time  in  40  persons  before  and  after  administration  of  calcium 
lactate,  has  arrived  at  the  same  conclusion.  Addis  (1909) 
found  that  calcium  salts  administered  by  mouth  increased  the 
ionizable  calcium  of  the  blood,  but  the  increase,  even  from  large 
doses,  was  considerably  less  than  that  required  to  alter  the  coagu- 
lability.    The  use  of  calcium  salts  as  local  hemostatics  is  a  failure. 

In  the  clotting  of  milk  by  rennet,  calcium  is  a  necessity.  (See 
Rennet.)  However,  if  much  of  an  alkaline  calcium  salt,  such 
as  in  lime-water,  is  added  to  milk,  the  alkalinity  will  check  the 
rennet  action  and  the  milk  will  not  coagulate.  It  is  probable 
that,  as  a  rule,  any  ordinary  amount  of  lime-water  is  neutralized 
by  the  acid  of  the  gastric  juice,  with  the  formation  of  calcium 
chloride. 

Januschke  (1910)  has  shown  that  pleural  effusions  may  be 
checked  by  subcutaneous  injection  of  calcium  chloride,  and 
Chiari  found  that  transudation  and  edema  were  favored  by  the  re- 
moval of  calcium,  which  normally  serves  to  check  the  permeabil- 
ity of  the  vessels.  These  experimenters  were  able  to  check 
pleural  effusion  resulting  from  diphtheria  toxin,  and  to  reduce 
the  conjunctival  edema  resulting  from  the  application  of  irri- 
tants. Other  authors  have  reported  good  results  from  the  use  of 
calcium  salts  in  serum-sickness  from  diphtheria  antitoxin,  in 
angioneurotic  edema,  in  chilblains,  and  in  other  conditions  sug- 
gesting abnormal  permeability  of  the  vessels. 

In  the  intestines  calcium  salts  have  been  found  to  retard  or 
check  peristalsis  and  to  prevent  the  action  of  some  of  the 
cathartics. 

Therapeutics. — Precipitated  chalk  is  used  largely  for  cleaning 
teeth.  Prepared  chalk  is  used  as  an  antacid  and  in.  diarrheal 
conditions.  Lime-water  is  used  as  an  addition  to  milk  to  render 
it  more  palatable  and  more  readily  borne  by  the  stomach,  and  to 
increase  its  calcium  content  for  growing  children.  Lime-water 
has  also  been  added  to  skin  lotions  for  eczema  and  dermatitis. 

Calcium  chloride  and  calcium  lactate  have  been  employed, 
with  questionable  results — (a)   In  hemorrhagic  conditions,  as 


94  PHARMACOLOGY  AND   THERAPEUTICS 

hemophilia,  the  purpuras,  the  hemorrhages  of  typhoid  fever  and 
tuberculosis,  melsena  neonatorum,  etc.  They  are  not  indicated 
unless  the  coagulability  of  the  blood  is  distinctly  reduced. 
(b)  In  tetany  and  the  nervous  manifestations  following 
parathyroidectomy  or  oxalic  acid  poisoning,  (c)  In  nervous 
diseases  with  hyperexcitability,  as  epilepsy,  (d)  In  serum  sick- 
ness, urticaria,  angioneurotic  edema,  chilblains,  pleurisy  with 
effusion,  etc.  (e)  In  bronchial  asthma,  to  lessen  nervous  ex- 
citability and  angioneurotic  swelling  of  the  bronchi. 

Either  the  lactate  or  chloride  may  be  used  in  dose  of  5-10 
grains  (0.3-0.7  gm.)  three  times  a  day.  The  bitter  saline 
taste  of  the  chloride  may  be  masked  by  peppermint.  Hypoder- 
matically,  a  4  per  cent,  solution  may  be  employed.  Intravenously, 
a  1  per  cent,  solution  of  the  chloride  may  be  given  in  amounts 
of  100  c.c,  or  a  0.2  per  cent,  solution  of  the  lactate  in  normal 
saline  in  amounts  up  to  500  c.c.  The  chloride  must  not  be 
confused  with  the  antiseptic,  chlorinated  lime  (chloride  of  lime). 

Calcium  Poisoning. — Large  doses  intravenously  at  first  in- 
crease the  contractility  of  the  heart,  but  soon  bring  about  its 
stoppage,  the  arteries  being  contracted  and  the  pupils  pin-point. 
Human  cases  are  not  reported. 

THE  ANTACIDS  NOT  OF  ALKALINE  REACTION 

These  do  not  neutralize  acids,  so  are  not  locally  antacid;  but 
in  the  blood  and  tissues  they  break  down  into  carbonates,  and  so 
increase  the  alkalescence  of  the  blood.  They  are,  therefore,  sys- 
temic alkalinizers.  These  compounds  are  the  acetic,  citric,  and 
tartaric  salts  of  potassium,  sodium,  and  lithium. 

The  potassium  and  sodium  acetates,  KC2H302,  NaC2H302,  and 
the  potassium,  sodium,  and  lithium  citrates,  K3-,Na3-,Li3,-C6H507, 
are  freely  soluble  in  water.  Potassium  bitartrate,  or  cream  of 
tartar  (KHC4H4O6),  is  of  acid  reaction,  and  soluble  in  200  parts 
of  water.  Potassium  and  sodium  tartrate,  or  Rochelle  salts 
(KNaC4H406),  is  very  feebly  alkaline  and  is  soluble  in  1.2  parts 
of  water. 

The  acetates  are  readily  absorbed,  and  are  alkalinizing  and 
diuretic.     Dose,  30  grains  (2  gm.). 

The  citrates  and  tartrates  are  absorbed  with  some  difficulty, 
and,  as  a  consequence,  are  more  or  less  cathartic.  A  portion, 
however,  is  absorbed,  and  this  acts  as  an  alkalinizer  and  diuretic. 
Tartrates  have  been  recovered  from  the  urine,  but  not  citrates. 

The  citrates  (see  Citric  Acid),  through  their  affinity  for  cal- 
cium, will  retard  or  prevent  the  coagulation  of  the  blood  and  the 
rennin  clotting  of  milk.  They  have  been  employed  without  any 
decided  success  in  the  late  weeks  of  typhoid  fever  to  lessen  the 


CARMINATIVES 


95 


tendency  to  thrombosis.  Lithium  citrate,  in  the  form  of  effer- 
vescing tablets, each  containing  5  grains  (0.3  gm.),has  been  much 
employed  to  make  a  palatable  effervescing  alkalinizing  drink. 
One  tablet  may  be  dissolved  in  a  glass  of  water.  Sodium  citrate, 
1  grain  (0.06  gm.)  to  each  ounce  (30  c.c.)  of  milk,  has  been  used 
in  infant- feeding  to  reduce  the  density  of  the  curd. 

Potassium  bitartrate  (cream  of  tartar)  is  not  readily  soluble 
in  water.  It  forms  Rochelle  salts  in  the  duodenum,  and  is 
laxative.     It  is  a  constituent  of  Imperial  drink.    (See  Citric  Acid.) 

The  hospital  "A.  B.  C.  mixture"  is  an  aqueous  solution  of 
which  each  teaspoonful  contains  10  grains  (0.7  gm.)  each  of  the 
acetate,  bicarbonate,  and  citrate  of  potassium. 

CARMINATIVES 

A  carminative  is  a  remedy  which  tends  to  overcome  flat- 
ulency, that  is,  distention  of  the  stomach  or  colon  with  gas. 
The  aromatics,  which  depend  for  their  action  upon  a  volatile 
oil  or  resinous  constituent,  form  the  great  bulk  of  the  class;  but 
alcohol,  the  distilled  liquors,  chloroform,  ether,  ammonia,  car- 
bonic acid,  as  in  mineral  waters  and  champagne,  and  many  other 
local  irritants  have  strong  carminative  properties.  We  shall 
take  up  here  the  action  of  the  aromatics. 

Pharmacologic  Action  of  the  Aromatics. — Microorganisms. — 
They  are  antiseptic,  some  of  them  strongly  so,  as  oil  of  eucalyptus. 
Their  use  as  antiseptics,  however,  is  very  limited,  because  of  their 
slight  solubility  in  water.  In  infected  tooth-cavities  the  dentists 
use  oil  of  cloves,  or  its  stearopten,  eugenol,  or  oil  of  cinnamon. 

Skin  and  Mucous  Membranes. — They  are  general  protoplasmic 
irritants,  so  are  irritant  to  both  skin  and  mucous  membranes. 
Applied  to  the  tongue  they  have  a  biting  effect,  and  in  the  eye 
cause  smarting.  Rubbed  into  the  skin  they  are  rubefacient, 
i.  e.,  produce  local  dilatation  of  the  skin- vessels,  with  redness  and 
warmth  of  the  part.  It  is  probable  that  they  also  stimulate  the 
sensory  nerve- endings  and  later  depress  them,  for  there  is  more  or 
less  biting  and  tingling,  followed  in  a  number  of  instances  by 
partial  anesthesia  or  numbness.  Peppermint,  and  its  stearopten 
menthol,  distinctly  depress  the  sensory  nerve-endings,  but  at  the 
same  time  stimulate  the  ends  of  the  temperature  nerves  which 
appreciate  cold  (Ioteyko,  1903),  hence  they  give  a  combined  feel- 
ing of  numbness  and  coolness. 

Alimentary  Tract. — Many  of  them  are  pleasantly  aromatic, 
and  these  are  used  as  flavors,  especially  in  the  dilute  forms  of  the 
official  waters  and  spirits.  They  tend  to  promote  the  appetite, 
but  in  undiluted  form  are  irritant  enough  to  induce  a  protective 


96  PHARMACOLOGY  AND  THERAPEUTICS 

flow  of  saliva.  In  the  stomach  they  are  local  irritants,  and  if 
given  in  sufficiently  concentrated  form,  dilate  the  vessels  and 
produce  hyperemia,  thus  giving  a  feeling  of  well-being  in  the  stom- 
ach region.  At  the  same  time  they  stimulate  motor  activity  and 
the  expulsion  of  accumulated  gases.  The  stronger  they  are,  the 
more  prompt  is  their  action.  It  is  generally  believed  that  there 
is  some  stimulation  of  secretion,  so  that  they  are  contraindicated 
in  hyperacidity;  but  Korczynski  (1901)  found  that  from  pepper 
and  mustard  there  was  not  only  no  increased  acidity  or  quantity 
of  the  gastric  juice,  but  even  a  diminution.  It  may  be  that, 
like  alcohol,  they  increase  the  gastric  secretion  through  an  action 
in  the  mouth.  There  seems  to  be  some  furtherance  of  absorp- 
tion by  the  stomach,  presumably  owing  to  the  active  hyperemia. 
Thus  the  functions  of  motion  and  absorption  are  stimulated, 
but  probably  not  that  of  secretion  unless  they  promote  appetite. 

On  the  intestine  there  is  a  reflex  effect,  and  Hertz  (19 10)  has 
observed  by  the  x-rays  that  very  promptly  following  the  ad- 
ministration of  a  strong  carminative  by  mouth  colon  peristalsis 
is  set  up.  This  is  a  reflex  action,  and  it  tends  to  cause  the  expul- 
sion of  accumulations  of  intestinal  gas,  and  to  overcome  colic 
or  griping.  For  this  last  action  these  drugs  are  regularly  added 
to  irritant  cathartics  as  "correctives." 

Absorption  is  rapid  from  stomach  and  duodenum. 

Nervous  System. — From  the  local  irritation  in  the  mouth  or 
stomach  there  is  a  general  reflex  stimulation  of  the  vasoconstric- 
tor, the  accelerator,  and  the  respiratory  centers,  so  that  respira- 
tion is  deepened  and  arterial  pressure  raised,  and  momentary 
feelings  of  faintness  are  overcome.  In  this  way  carminatives 
act  as  restoratives.  There  is  also,  after  absorption,  an  apparent 
cerebral  stimulation  which  may  be  effective  in  overcoming  hys- 
teria and  other  conditions  of  nervous  instability. 

Circulation. — Besides  the  reflex  stimulation,  there  is  flushing 
of  the  skin  from  dilatation  of  the  cutaneous  arterioles. 

Genital  Organs. — In  strong  doses  these  oils  tend  to  be  em- 
menagogue  and  abortifacient,  and  many  of  the  cases  of  poisoning 
by  pennyroyal,  rue,  savine,  and  tansy  have  come  from  attempts 
to  produce  miscarriage.  Frequently  the  victim  has  died  in 
agony  without  the  abortion  occurring,  or  has  developed  a  severe 
colitis.  Whether  the  influence  on  the  genital  organs  could  be  a 
factor  in  overcoming  hysteria  has  not  been  studied. 

Elimination. — Part  is  oxidized  in  the  body,  and  the  remainder 
is  eliminated  in  the  urine  and  the  breath,  mostly  in  more  or  less 
changed  aromatic  forms.  For  example,  the  odor  of  the  breath 
of  the  whisky-drinker  is  not  that  of  either  alcohol,  whisky,  or 
fusel  oil,  but  of  a  derivative  of  the  fusel  oil.     The  urine  from 


CARMINATIVES  97 

turpentine  has  an  odor  of  violets,  and  that  after  peppermint  is 
strongly  aromatic,  but  not  minty.  In  the  elimination  there  is  a 
remote  local  irritant  action  on  the  kidneys  and  bronchi,  with 
diuretic  and  expectorant  effects.  The  urine  may  even  be 
rendered  antiseptic,  but  it  is  a  question  whether  large  enough 
amounts  ever  appear  in  the  bronchial  mucus  to  have  an  antiseptic 
value. 

Toxicology. — Poisoning  results — (a)  from  the  irritant  ones 
in  concentrated  form,  with  local  and  systemic  symptoms,  or  (b) 
from  absorption,  with  systemic  symptoms  only.  From  the  very 
irritant  types  there  may  be  violent  gastritis  and  colitis,  with 
vomiting,  diarrhea,  and  abdominal  cramps,  and  perhaps  vomiting 
of  blood  and  bloody  stools.  From  absorption  there  may  be 
overstimulation  of  the  cerebrum,  with  excitement,  great  restless- 
ness, delirium,  and  perhaps  cerebral  convulsions,  or  there  may  be 
dizziness,  stupor,  and  mental  depression  similar  to  that  from 
alcohol  or  ether.  These  states  may  pass  into  collapse,  coma, 
the  convulsions  of  asphyxia,  and  death.  The  kidneys  may  be  the 
seat  of  an  acute  nephritis.  The  treatment  is  to  empty  the  stom- 
ach and  administer  demulcents,  such  as  white  of  egg,  milk,  olive 
oil,  and  mucilaginous  drinks,  and  to  treat  symptomatically  for 
collapse.  The  inflammatory  lesions  must  be  treated  as  when  they 
arise  from  other  causes.  After  recovery  from  the  acute  symptoms 
there  may  be  a  chronic  nephritis  or  colitis.  Poisoning  has  been 
reported  from  asafetida,  nutmeg,  mustard  and  a  great  many  of 
the  aromatics.  The  colitis  cases  have  mostly  resulted  from  the 
emmenagogue  oils  taken  for  abortifacient  purposes. 

Therapeutics. — A  number  of  carminative  drugs  have  other 
striking  actions  for  which  they  are  of  importance  in  therapeutics, 
and  these  we  shall  study  in  detail  elsewhere.  The  following  are 
arranged  in  therapeutic  groups: 

1.  As  anticolics  (in  intestinal  and  uterine  cramps).  Espe- 
cially employed  for  infants  are  anise,  peppermint,  and  dill  water, 
and  for  adults  the  distilled  liquors,  essence  of  ginger,  spirit  of 
peppermint,  aromatic  spirit  of  ammonia,  and  Hoffmann's  anodyne 
(the  compound  spirit  of  ether). 

2.  As  odors  and  flavors — anise,  bitter  almond,  caraway,  cinna- 
mon, coriander,  fennel,  lavender  flowers,  lemon,  nutmeg,  orange- 
peel,  peppermint,  spearmint,  rose,  and  vanilla.  Of  the  waters, 
the  dose  is  i  dram  (4  c.c);   of  the  spirits,  5  minims  (0.3  c.c). 

3.  .4s  correctives  of  irritant  cathartics — the  oils  of  anise,  cara- 
way, cloves,,  coriander,  fennel,  and  peppermint.  Of  the  oil, 
yi  minim  (0.015  c.c);  or  of  the  drug,  1  grain  (0.06  gm.),  to  each 
dose. 

4.  For  tympanites,  as  in  typhoid  fever,  pneumonia,  or  follow- 

7 


98  pharmacology  and  therapeutics 

ing  operations.  By  mouth,  oil  of  turpentine,  10  minims  (0.07 
c.c.)  in  capsule,  or  asafetida,  5  grains  (0.03  gm.)  in  pill  or  tincture. 
By  rectum,  oil  of  turpentine,  y2  ounce  (15  c.c),  or  tincture  of 
asafetida,  1  dram  (4  c.c),  added  to  a  soapsuds  enema  or  to  8 
ounces  or  more  of  infusion  of  chamomile  (an  aromatic  bitter). 

5.  As  anthelmintics — oil  of  chenopodium  for  round  worms  and 
oil  of  thyme  or  thymol  for  hookworms. 

6.  As  stimulants  to  mucous  membranes  of  nose  and  throat — 
eucalyptol,  camphor,  and  menthol,  mixed  together  and  inhaled, 
or  diluted  with  liquid  petrolatum  and  used  as  a  spray. 

7.  As  antiseptics  and  anesthetics — oil  of  cloves  or  oil  of  cinna- 
mon in  decayed  tooth,  a  drop  on  cotton.  Eugenol,  the  stearopten 
of  oil  of  cloves,  is  also  used. 

8.  As  counterirritanls — camphor,  capsicum,  and  menthol, 
and  the  oils  of  mustard,  rosemary,  and  turpentine. 

g.  As  stimulants  in  chronic  skin  diseases,  such  as  eczema — the 
oils  of  cade  and  tar  in  the  form  of  ointment. 

10.  As  stimulants  to  the  growth  of  hair — the  oil  of  mace. 

11.  As  antirheumatics — methyl  salicylate  and  the  oils  of  birch 
and  wintergreen,  externally  as  a  liniment,  and  internally  in  5- 
minim  (0.3  c.c.)  capsules. 

12.  As  antihysterics — asafetida,  camphor,  musk,  sumbul, 
and  valerian. 

13.  As  anti-asthmatics — powdered  cubebs  smoked  in  cigaret 
form. 

14.  As  bronchial  stimulants  [and  perhaps  antiseptics) — 
creosote,  5  minims  (0.3  c.c),  oil  of  turpentine,  10  minims  (0.7 
c.c),  terebene,  10  minims  (0.7  c.c),  and  syrup  of  tar,  10  minims 
(1  c.c). 

15.  As  diuretics — oil  and  spirit  of  juniper;  the  nuidextracts 
of  buchu  and  uva-ursi,  1  dram  (4  c.c). 

16.  As  urinary  antiseptics — the  oils  of  copaiba,  cubebs,  and 
sandalwood,  and  balsam  of  copaiba,  5  minims  (0.3  c.c). 

17.  As  emmenagogues — apiol,  from  oil  of  parsley,  and  the  oils 
of  pennyroyal,  rue,  savine,  and  tansy,  3  minims  (0.2  c.c). 

18.  In  leprosy — chaulmoogra  oil,  5  minims  (0.3  c.c),  two  or 
three  times  a  day. 

A  number  of  these  will  be  referred  to  elsewhere  in  their 
respective  therapeutic  groups. 

For  simple  carminative  action  the  spices  are  much  used,  and 
usually  in  combinations  of  several  carminatives,  as  in  the  com- 
pound tinctures,  compound  spirits,  and  the  aromatic  fluidextract. 
A  favorite  hospital  dose  for  flatulence  is  compound  spirit  of  ether, 
aromatic  spirit  of  ammonia,  compound  tincture  of  lavender,  and 
spirit  of  chloroform,  of  each,  15  minims  (1  c.c). 


CARMINATIVES  99 

Preparations. — i.  The  official  volatile  oils  (the  Latin  name  is 
given  in  the  genitive)  are:  Allspice  (pimentae),  anise  (anisi), 
birch  (betulae),  bitter  almond  (amygdalae  amarae),  cade  (cadini), 
cajuput  (cajuputi),  caraway  (cari),  chenopodium  (chenopodii) , 
cinnamon  (cinnamomi),  cloves  (caryophylli),  copaiba  (copaibae), 
coriander  (coriandri),  cubeb  (cubebae),  erigeron  '  (erigerontis) , 
eucalyptus  (eucalypti),  fennel  (fceniculi),  juniper  (juniperi), 
lavender  (lavandulae  riorum),  lemon  (limonis),  mustard  (sinapis), 
nutmeg  (myristicas) ,  orange-peel  (aurantii  corticis),  pennyroyal 
(hedeomae),  peppermint  (menthae  piperitae),  rose  (rosae).  rosemary 
(rosmarini),  sandalwood  (santali),  sassafras  (sassafras),  savin 
(sabinae),  spearmint  (menthae  viridis),  tar  (picis  liquidae),  thyme 
(thymi),  turpentine  (terebinthinae) ,  wintergreen  (gaultheriae) . 

2.  The  waters  (aquae)  are:  Anise,  bitter  almond,  camphor, 
cinnamon,  fennel,  orange-flower  (aurantii  riorum),  stronger 
orange-flower  (aurantii  riorum  fortioris),  peppermint,  rose, 
stronger  rose,  spearmint. 

3.  The  spirits  (spiritus) — the  simple  are:  Bitter  almond  of 
1  per  cent,  strength,  dose,  8  minims  (0.5  c.c);  of  10  per  cent, 
strength,  camphor,  cinnamon,  peppermint,  and  spearmint;  of 
5  per  cent,  strength,  juniper,  lavender,  and  wintergreen.  The 
compound  are  aromatic  ammonia  (ammonia,  lemon,  lavender, 
and  nutmeg) ,  compound  ether  (ethereal  oil  and  ether) ,  compound 
juniper  (juniper,  caraway,  fennel),  and  compound  orange  (orange- 
peel,  lemon,  coriander,  anise). 

4.  The  Elixirs. — These  are  sweetened  and  aromatic,  more  or 
less  alcoholic  liquids.  Aromatic  elixir  (elixir  aromaticum)  con- 
tains the  compound  spirit  of  orange,  and  the  elixir  adjuvans  is 
aromatic  elixir  with  the  addition  of  12  per  cent,  of  fluidextract 
of  licorice.  The  liqueurs  and  cordials,  as  creme  de  menthe, 
absinthe,  Benedictine,  etc.,  are  elixirs.     (See  Alcohol.) 

5.  Stearoptens  used  by  themselves  are:  Benzaldehyde,  from 
oil  of  bitter  almonds;  cinnaldehyde,  from  oil  of  cinnamon; 
eucalyptol,  from  oil  of  eucalyptus;  eugenol,  from  oil  of  cloves; 
menthol,  from  oil  of  peppermint;  methyl  salicylate,  from  oil  of 
birch  or  wintergreen,  and  also  manufactured  synthetically; 
safrol,  from  oil  of  sassafras,  and  camphor. 

6.  The  Spices. — The  spices  are  not  only  aromatic,  but  more 
or  less  hot  and  biting.  Some  of  them  yield  no  oil  and  depend  for 
their  action  on  resinous  ingredients.  They  are  allspice  (pimentae), 
calamus  (calami),  cinnamon,  cardamom,  cloves  (caryophylli), 
ginger  (zingiberis) ,  black  pepper  (piperis),  and  red  pepper 
(capsici) . 

7.  The  simple  aromatic  tinctures  are:  Asafetida,  bitter  orange- 
peel  (aurantii  amari),  sweet  orange-peel  (aurantii  dulcis),  capsi- 


IOO  PHARMACOLOGY  AND  THERAPEUTICS 

cum,  cardamom,  cinnamon,  ginger,  lemon-peel  (limonis  corticis), 
musk  (moschi),  valerian,  vanilla. 

8.  The  compound  tinctures  are:  Compound  tincture  of  carda- 
mom (tinctura  cardamomi  composita),  containing  cardamom, 
cinnamon,  and  caraway. 

Compound  tincture  of  lavender  (tinctura  lavandulae  composita) , 
containing  oil  of  lavender,  oil  of  rosemary,  cinnamon,  cloves,  and 
nutmeg. 

Ammoniated  tincture  of  valerian,  a  tincture  of  valerian  made 
with  aromatic  spirit  of  ammonia  as  the  menstruum. 

9.  The  fluidextr acts  are:  Bitter  orange-peel,  buchu,  calamus, 
capsicum,  cubebs,  cypripedium,  eucalyptus,  ginger  (zingiberis) , 
savine,  sumbul,  uva-ursi,  valerian,  and  the  aromatic  fluidextract 
(fluidextractum  aromaticum).  The  last  is  a  fluidextract  of  aro- 
matic powder  (pulvis  aromaticus)  which  contains  cinnamon  and 
ginger,  each,  35  parts,  and  cardamom  and  nutmeg,  each,  15  parts. 

Doses. — These  vary  somewhat.  Where  the  drugs  have  no 
other  marked  quality,  their  carminative  doses  are:  Powdered 
drug,  15  grains  (1  gm.);  oils,  5  minims  (0.3  c.c);  waters,  1  dram 
(4  c.c.) ;  spirits,  10-30  minims  (0.7-2  c.c.) ;  tinctures,  30  minims 
(2  c.c);  aromatic  fluidextract,  30  minims  (2  c.c). 

BITTERS 

These  are  substances  that  are  employed  to  give  a  bitter  taste, 
the  object  of  their  administration  being  to  improve  the  appetite. 
When  the  appetite  is  below  normal,  a  strong  stimulation  of  the 
taste-buds  will  often  restore  it;  and  substances  with  a  bitter 
taste  that  is  not  otherwise  disagreeable  tend  to  act  as  stimulants 
to  the  taste-buds. 

That  appetite  is  important  for  digestion  has  been  demon- 
strated by  Pawlow  and  his  followers.  They  discovered  that  the 
stomach  of  a  hungry  dog  would  secrete  gastric  juice  if  he  saw  or 
smelled  food,  even  though  there  was  no  food  in  the  stomach. 
They  called  this  the  "appetite"  or  "psychic"  gastric  juice. 
They  also  found  that  some  foods  would  not  digest  at  all, — for 
example,  white  of  egg, — if  they  were  put  in  the  empty  stomach 
without  arousing  the  appetite,  as  through  a  fistula  while  the 
animal  slept.  That  is,  they  were  incapable,  by  direct  action  on 
the  stomach-wall,  of  inducing  the  stomach  to  secrete.  But 
Pawlow  noted  further  that,  on  showing  the  dog  food,  the  appetite 
juice  would  form  and  would  act  on  the  egg-albumin;  and  that 
the  products  of  this  primary  digestion  would  then  stimulate  the 
stomach-wall  and  induce  the  secretion  which  continued  the  diges- 
tion.    Hence  the  appetite  juice  is  of  great  importance  in  starting 


ANTI-BITTERS  IOI 

digestion;  and  since  the  formation  of  the  appetite  juice  is  favored 
by  bitters,  these  may  be  considered  aids  to  digestion  in  atonic  cases. 

The  bitter  effect  on  appetite  is  solely  the  local  one  on  the  taste- 
buds,  so  it  is  not  obtained  if  the  bitter  is  hidden,  as  in  capsules 
or  gelatin-coated  pills,  or  if  it  is  disguised  by  sweetening  agents 
or  flavors.  It  requires  for  its  development  that  the  bitter  shall 
be  taken  just  preceding  the  usual  time  for  eating;  that  is,  from 
ten  to  twenty  minutes  before.  If  the  appetite  is  already  normal, 
the  bitter  may  not  increase  it,  and  may  even  lessen  it.  If  the 
stomach  and  bowels  are  deranged,  a  bitter  may  nauseate. 

The  bitters  are  classed  as  the  simple  bitters,  which  have  no 
effect  on  taste  other  than  bitterness,  and  the  aromatic  bitters, 
which,  in  addition  to  the  bitter  principle,  contain  a  volatile  oil 
or  resinous  aromatic. 

The  simple  bitters  are:  barberry  (berberis),  calumba,  con- 
durango,  dandelion  (taraxacum),  gentian,  and  quassia.  These 
may  be  used  in  the  form  of  an  infusion,  dose,  y2  ounce  (15  c.c.), 
or  tincture,  dose,  1  dram  (4  c.c),  diluted  to  give  a  bitter  drink. 
The  powerful  pharmacologic  drugs,  nux  vomica,  with  its  alkaloid, 
strychnine,  and  cinchona,  with  its  alkaloid,  quinine,  are  often 
employed  also  as  simple  bitters.  Quassia-cups  are  used  in  some 
households.  They  are  turned  out  of  quassia  wood  and  impart 
an  intense  bitterness  to  water  allowed  to  stand  in  the  cup  for 
fifteen  minutes.  The  cups  retain  their  power  for  a  long  time. 
Infusion  of  quassia  is  also  employed  as  a  bitter  and  as  an  enema 
for  pin- worms. 

Orexine  hydrochloride  and  tannate,  bitter,  crystalline  bodies, 
are  also  used  in  dose  of  5  grains  (0.3  gm.).  They  are  soluble  in 
about  15  parts  of  water. 

The  aromatic  bitters  are:  wormwood  or  vermouth  (absinthi- 
um), chamomile  (anthemis),  German  chamomile  (matricaria), 
bitter  orange-peel,  and  serpentaria. 

There  are  two  aromatic  bitter  tinctures  which  are  favorite 
appetizers,  viz.,  compound  tincture  of  gentian  (tinctura  gentianas 
composita),  made  of  gentian,  cardamom,  and  bitter  orange-peel, 
dose,  1  dram  (4  c.c),  and  compound  tincture  of  cinchona  (tinctura 
cinchonas  composita),  made  of  red  cinchona,  serpentaria,  and 
bitter  orange-peel,  dose,  1  dram  (4  c.c). 

ANTI-BITTERS 

There  are  two  vegetable  substances  that  possess  the  peculiar 
property  of  abolishing  the  appreciation  of  bitter  taste.  They  are 
verba  santa  (eriodictyon),  a  leaf,  and  gymnemic  acid,  a  whitish 
powder  which  is  soluble  in  water;  dose,  5  grains  (0.3  gm.). 


102  PHARMACOLOGY  AND  THERAPEUTICS 

The  syrup  of  yerba  santa,  dose,  i  dram  (4  ex.),  has  been 
much  employed  as  an  addition  to  bitter  medicines,  especially 
quinine.  It  lessens  the  appreciation  of  bitter  taste,  but  in  swal- 
lowing hardly  acts  rapidly  enough  to  check  the  taste  of  a  bitter 
substance  mixed  with  it;  in  fact,  to  get  the  real  anti-bitter  effect, 
it  is  necessary  to  hold  the  yerba  santa  preparation  in  the  mouth 
for  several  minutes  before  the  bitter  is  taken.  Yerba  santa  is 
itself  bitter  and  very  astrigent.  It  contains  tannic  acid  in 
abundance,  and  it  is  largely  by  forming  the  insoluble  tannate  that 
it  lessens  the  bitterness  of  quinine  and  other  alkaloids. 

CHARCOAL 

Animal  charcoal  (carbo  animalis)  is  prepared  from  bones, 
and  85  per  cent,  of  it  consists  of  mineral  matter.  It  is  called 
"bone-black."  Purified  animal  charcoal  is  bone-black  boiled 
with  hydrochloric  acid  and  washed  thoroughly  with  water.  It 
is  almost  pure  carbon.  Wood  charcoal  (carbo  ligni)  is  prepared 
from  soft  wood;  it  is  nearly  pure  carbon.  Dose  of  charcoal, 
15  grains  (1  gm.). 

Purified  animal  charcoal  possesses  the  power,  in  a  high  degree, 
of  absorbing  organic  colors,  hence  is  used  largely  in  pharmacy 
and  the  arts  for  decolorizing,  as  in  the  refining  of  sugar  and 
petroleum.  It  has  also  a  certain  amount  of  power  to  remove 
certain  resins,  bitter  principles,  and  alkaloids  from  their  solu- 
tions, and  Lebourdais  has  in  this  way  recovered  digitalin,  colo- 
cynthin,  strychnine,  quinine,  and  other  active  principles.  Owing 
to  this  property,  it  has  been  proposed  as  a  remedy  in  mushroom 
poisoning,  arsenic  poisoning,  strychnine  poisoning,  etc.,  }4  ounce 
(15  gm.)  being  the  dose  for  each  grain  of  strychnine  salt  swal- 
lowed. Unfortunately,  this  property  of  absorption  cannot  be 
depended  upon.  Wood-charcoal  and  bone-black  are  very  infe- 
rior as  absorb  ents. 

In  medicine,  wood-charcoal  has  been  used  in  flatulency  be- 
cause of  its  known  power  of  absorbing  gases.  But  when  satu- 
rated with  liquid,  it  loses  this  power  of  gas  absorption,  hence 
in  fermenting  stomach-contents  is  of  little  or  no  value.  In  the 
study  of  the  stools  it  is  much  employed  in  timing  the  passage 
through  the  alimentary  tract.  A  dose  of  30  grains  (2  gm.) 
given  with  a  meal  will  color  the  stool  resulting  from  that  meal 
black  or  gray-black. 

EMETICS 

These  are  drugs  employed  to  induce  vomiting.  To  produce 
emesis   requires   the   coordination   of   several   mechanisms,  the 


EMETICS  103 

following  actions  being  necessary;  viz.,  closure  of  the  pylorus, 
opening  of  the  cardia,  setting  or  contraction  of  the  diaphragm, 
and  contraction  of  the  abdominal  muscles.  If  the  pylorus  re- 
mains open,  the  result  is  "retching."  The  coordination  is  pre- 
sided over  by  the  vomiting-center  situated  in  the  medulla 
oblongata.  This  center  is  highly  sensitive  to  certain  sensory 
impulses  from  the  stomach,  and  is  also  capable  of  being  directly 
stimulated  by  certain  substances  in  the  circulating  blood.  The 
emetic  measures  in  common  use  may  be  divided  into  the  local  or 
reflex  emetics  and  the  central  emetics. 

1.  The  reflex  emetics  act  by  irritating  the  throat  or  stomach, 
and  are:  tickling  the  throat  with  a  feather,  or  sticking  the  finger 
down  the  throat,  or  swallowing  one  of  the  following:  a  large 
draft  of  lukewarm  water;  alum,  30  grains  (2  gm.);  copper  sul- 
phate, 30  grains  (2  gm.);  zinc  sulphate,  15  grains  (1  gm.); 
ipecac,  15  grains  (1  gm.);  tartar  emetic,  2  grains  (0.13  gm.); 
yellow  subsulphate  of  mercury  or  turpeth  mineral,  2  grains  (0.13 
gm.);  mustard,  one  tablespoonful  (about  10  gm.).  The  drugs 
mentioned  are  all  irritants,  and  may  do  great  harm  to  the  stomach 
if  vomiting  fails  to  come  on;  hence  the  dose  should  not  be  given 
more  than  twice. 

2.  The  only  central  emetic  in  common  use  is  apomorphine 
chloride,  apomorphine  being  an  alkaloid  derived  from  morphine 
by  dehydration.  It  is  soluble  in  40  parts  of  water  or  alcohol, 
deteriorates  and  turns  green  on  exposure  to  light  and  air,  and  is 
considered  unfit  for  use  if  on  being  shaken  with  a  little  water  it 
imparts  at  once  an  emerald-green  tint.  The  emetic  dose  by 
hypodermatic  is  yw  grain  (0.006  gm.),  and  the  expectorant  dose  is 
¥V  grain  (0.002  gm.). 

Quite  quickly,  after  a  hypodermatic  injection  of  apomorphine, 
nausea  comes  on,  and  then,  in  about  five  minutes,  copious  vomit- 
ing. The  drug  is  not  at  all  excreted  into  the  stomach,  and  it 
acts  upon  the  center  directly.  Smaller  doses  are  expectorant, 
increasing  and  fluidifying  the  bronchial  mucus,  probably  by  a 
nauseant  action.  Small  doses  are  said  to  have  a  mild,  morphine- 
like  effect  in  promoting  sleep;  but  in  the  author's  tests  on  16 
patients  for  several  successive  nights,  though  -^V  grain  (0.003 
gm.)  proved  hypnotic,  every  patient  was  nauseated. 

Therapeutics  of  Emetics. — 1.  To  empty  the  stomach — as 
in  acute  indigestion,  alcoholism,  the  ingestion  of  poisons,  etc. 

2.  To  remove  an  obstruction  from  the  esophagus  or  respira- 
tory passages. 

3.  To  loosen  a  ball- valve  gall-stone  in  the  biliary  passages 
(nature's  way). 


104  PHARMACOLOGY  AND    THERAPEUTICS 

4.  To  relieve  spasm  or  marked  congestion  in  the  respiratory 
passages,  as  in  croup  or  severe  asthma. 

Apocodeine,  an  alkaloid  prepared  from  codeine,  has  a  different 
action.  It  is  employed  somewhat  in  the  laboratory  as  a  general 
paralyzant  of  sympathetic  nerve-endings.  In  this  respect  it 
directly  antagonizes  epinephrine.  In  therapeutics  it  has  been 
used  slightly  hypodermatically  in  dose  of  y2  grain  (0.03  gm.) 
to  promote  intestinal  peristalsis.  It  acts  by  cutting  off  splanch- 
nic control  of  intestinal  activity  through  the  depression  of  the 
sympathetic  nerve-endings,  but  is  not  a  safe  drug  nor  a  very 
efficient  one  for  the  purpose. 

ANTEMETICS 

These  are  remedies  designed  to  check  nausea  and  vomiting. 
In  the  treatment  of  nausea  and  vomiting  the  recumbent  position 
should  be  maintained.     The  antemetics  are: 

1.  Antacids,  to  check  the  irritation  of  hyperacidity;  especially 
sodium  bicarbonate,  20  grains  (1.3  gm.),  and  milk  of  magnesia, 
2  drams  (8  gm.). 

2.  Carminatives — Champagne,  brandy,  chloroform  water, 
essence  of  ginger,  spirit  of  peppermint,  menthol,  etc.  In  alcoholic 
nausea  and  vomiting  strong  hot  carminative  mixtures  are  indi- 
cated.    (See  Alcohol.) 

3.  Protectees — which  mechanically  prevent  irritation  of  the 
mucous  membrane,  as:  Bismuth  subnitrate,  bismuth  subcar- 
bonate,  bismuth  subgallate,  and  cerium  oxalate,  dose  of  each, 
30  grains  (2  gm.). 

4.  Local  sedatives,  those  which  depress  the  sensory  nerve- 
endings:  Tincture  of  belladonna,  15  minims  (1  c.c),  atropine 
sulphate,  yfo  grain  (0.0006  gm.),  cocaine  hydrochloride,  %  grain 
(0.015  gm.),  orthoform,  5  grains  (0.3  gm.),  anesthesin,  5  grains 
(0.3  gm.),  phenol,  3  grains  (0.2  gm.),  and  cracked  ice. 

5.  Central  sedatives — Bromides,  chloral  hydrate,  chloretone, 
codeine,  morphine,  sulphonal,  veronal,  and  to  some  extent  other 
narcotics. 

6.  Counterirritants  to  the  epigastrium,  as  a  hot-water  bag, 
an  ice-bag,  a  mustard  plaster,  or  the  actual  cautery. 

The  nausea  of  pregnancy  and  that  of  seasickness  are  espe- 
cially resistant  to  treatment.  In  pregnancy,  alkalies  given  at 
the  height  of  digestion  or  before  going  to  bed,  and  sometimes 
a  light  breakfast  before  arising,  may  be  effective.  Atropine  or 
bromides  or  cerium  oxalate  in  large  doses  may  also  be  tried. 
Frequently  no  measures  are  entirely  satisfactory.  Persistent 
vomiting  in  pregnancy  is  a  serious  toxic  manifestation,  usually 


ASTRINGENTS 


io5 


requiring  the  termination  of  the  pregnancy.  The  cause  of  the 
vomiting  may  be  acidosis  or  acetonuria,  and  these  are  an  indica- 
tion for  abundance  of  alkalies  and  carbohydrate  food. 

In  seasickness  the  recumbent  position  on  deck,  with  eyes  pro- 
tected so  that  the  rolling  of  the  vessel  is  not  seen,  is  often  effective. 
Another  effective  measure  is  thorough  purgation  with  calomel 
or  compound  cathartic  pills  before  sailing,  and  every  two  or 
three  days  during  the  voyage.  The  avoidance  of  much  liquid, 
such  as  soup,  and  of  tobacco,  is  also  recommended.  Bromides, 
chloral  hydrate,  veronal,  chloretone,  champagne,  and  iced 
brandy  are  employed  with  varying  success.  A  much-vaunted, 
and  at  times  an  exceedingly  satisfactory,  prophylactic  remedy  is 
strychnine  sulphate,  yio  grain  (0.0005  gm-)>  and  hyoscine  hydro- 
bromide,  -2T0  grain  (0.00025  gm.),  every  hour  for  five  doses  before 
sailing,  and,  if  necessary,  repeated  every  day  during  the  trip. 
A  hypodermic  of  strychnine  sulphate,  ■£$  grain  (0.002  gm.), 
and  atropine  sulphate,  Tio  grain  (0.0006  gm.),  will  sometimes 
bring  about  a  striking  improvement  in  the  patient's  comfort. 

ASTRINGENTS 

These  are  drugs  which  tend  to  shrink  mucous  membranes  or 
raw  tissues.  Astringents  produce  their  effects:  (1)  By  con- 
striction of  arterioles,  as  epinephrine  and  cocaine;  (2)  by  ab- 
straction of  water,  as  glycerin  and  alcohol;  and  (3)  by  chemic 
precipitation  of  the  superficial  layers  of  protein,  as  the  metallic 
and  vegetable  astringents. 

The  most  employed  metallic  astringents  are:  Alum,  silver 
nitrate,  ferric  chloride,  ferric  subsulphate  (MonselPs  salt),  zinc 
sulphate,  and  copper  sulphate.     (See  Metals.) 

Potassium  chlorate  in  saturated  aqueous  solution  (1:16)  is 
employed  in  relaxed  sore  throat  and  in  stomatitis,  especially  that 
from  mercury.  It  has  been  used  both  internally  and  locally, 
but  its  sole  value  is  due  to  the  local  astringency. 

It  is  capable  of  causing  severe  irritation  of  the  gastroin- 
testinal tract,  methemoglobinemia,  and  albuminuria,  but  Buri 
states  that  this  takes  very  large  doses.  Bachem  (191 2)  gave 
1  ounce  (30  gm.)  daily  for  six  weeks  to  pups,  and  there  was  no 
effect  on  growth  rate,  kidneys,  stomach,  or  blood.  The  drug 
was  rapidly  eliminated  in  the  urine,  and  acted  as  any  other 
indifferent  salt.  Fifteen  grains  (1  gm.)  have  caused  death  in  a 
child;  1  ounce  (30  gm.)  has  been  taken  without  symptoms. 
Mercier  (1902)  reports  death  in  a  child  of  three  years,  eighteen 
hours  after  taking  "a  pinch  or  two "  of  the  chlorate.  At  autopsy 
the  blood  and  bone-marrow  had  a  prune- juice  appearance  and 


106  PHARMACOLOGY  AND    THERAPEUTICS 

contained  methemoglobin;  the  bladder  was  filled  with  dark- 
brown  urine. 

Potassium  chlorate  mixed  dry  with  sulphur,  hypophosphites, 
and  oxidizable  organic  matters,  is  likely  to  explode.  In  the 
form  of  tablets  it  has  frequently  caused  fire  on  contact  with  sul- 
phur matches. 

The  vegetable  astringents  contain  either  resins  or  tannic 
acid.  The  resinous  astringents  are  myrrh,  a  tincture  of  which, 
diluted  with  water,  is  used  for  soft  and  bleeding  gums,  and 
Hydrastis,  whose  tincture,  diluted  with  water,  is  used  locally 
in  vaginitis  and  urethritis. 

The  tannic-acid  astringents  are:  blackberry  root  (rubus), 
catechu,  galls,  gambir,  geranium,  kino,  krameria,  logwood 
(hematoxylon) ,  oak-bark  (quercus),  rosa  gallica,  sumac  fruit 
(rhus  glabra) ,  and  witch-hazel  bark  (hamamelis) . 

Preparations  and  Doses. — Extracts — Logwood,  15  grains 
(1  gm.),  krameria,  f}4  grains  (0.5  gm.). 

Fluidextracts — Blackberry,  geranium,  krameria,  oak,  rose, 
sumac  (rhois  glabrae),  witch-hazel  (hamamelidis  foliorum);  dose, 
15  minims  (1  c.c). 

Tinctures — Kino  and  compound  gambir,  each,  5  per  cent.; 
and  galls  and  krameria,  each,  20  per  cent. ;  dose,  30  minims  (2  c.c). 

Syrup  of  krameria,  45  per  cent;  dose,  i.dram  (4  c.c). 

Troches  of  krameria,  each,  1  grain  (0.06  gm.). 

TANNIC  ACID  OR  TANNIN  (Acidum  Tannicum) 

This  substance  is  prepared  from  nutgalls.  It  is  slowly  but 
completely  soluble  in  less  than  its  own  weight  of  water  or  alcohol, 
and,  with  the  aid  of  heat,  in  its  own  weight  of  glycerin.  It  is 
used  locally  in  5  to  20  per  cent,  preparations,  or  internally  in  dose 
of  5  grains  (0.3  gm.).  The  ointment,  the  glycerite,  and  styptic 
collodion  are  of  20  per  cent,  strength.  The  troches  contain  1 
grain  (0.06  gm.)  in  each.  Tannic  acid  is  incompatible  with 
alkaloidal  salts,  metallic  salts,  such  as  mercuric  chloride,  lime- 
water,  gelatin,  and  protein.  The  precipitation  of  the  gelatin 
and  proteins  of  hides  is  "tanning,"  and  changes  the  hides  into 
leather.  In  like  manner  tannic  acid  renders  insoluble  the  coatings 
of  gelatin  capsules  and  pills. 

Its  astringency  depends  upon  its  power  to  precipitate  the 
proteins  of  the  superficial  cells,  thus  causing  shrinking  of  the 
tissues  and  stoppage  of  secretion.  It  checks  small  hemorrhages, 
i.  e.,  is  hemostatic  or  styptic,  by  coagulating  the  blood.  In  the 
stomach  it  precipitates  the  proteins  of  the  food,  but  these  re- 
dissolve  in  the  gastric  juice.  Its  effect  on  mucous  membranes 
is  to  check  secretion.     Strasburger  believes  that  the  lessening  of 


ANTHELMINTICS 


IO7 


intestinal  mucus  by  astringents  results  in  a  great  diminution  in 
the  number  of  bacteria  in  the  feces.  In  the  intestines  free  tannic 
acid  is  constipating,  but  it  soon  changes  to  sodium  tannate  and 
then  to  sodium  gallate,  which  is  not  astringent.  It  is  absorbed 
and  excreted  as  sodium  gallate,  and  has  no  astringent  or  styptic 
power  after  absorption.  Because  of  the  rapid  disappearance  of 
tannic  acid  from  the  intestines,  preparations  of  the  vegetable 
drugs  are  preferred  in  diarrhea,  the  colloid  and  other  extractive 
vegetable  matters  tending  to  retard  the  chemic  changes  and  ab- 
sorption of  the  tannic  acid.  If  in  too  concentrated  form,  tannic 
acid  is  an  irritant. 

Therapeutics. — 1.  To  harden  the  skin,  as  in  threatened  bed- 
sore. 

2.  As  a  gargle  or  swab  in  relaxed  sore  throat. 

3.  As  a  hemostatic  for  small  accessible  hemorrhages. 

4.  As  chemic  antidote  in  poisoning  by  alkaloidal  and  metal- 
lic salts,  especially  those  of  antimony,  with  which  it  forms  a  very 
insoluble  substance. 

5.  In  the  form  of  suppository,  each  containing  5  grains  (0.3 
gm.),  in  prolapse  of  the  rectum  or  bleeding  internal  hemorrhoids. 

6.  In  diarrhea — the  vegetable  astringents. 

Tannigen  (diacetyltannin) ,  tannoform  (formaldehyde-tannin), 
tannopin  (hexamethylenamine-tannin),  and  tannalbin  (egg- 
albumin  tannate)  are  all  compounds  marketed  for  diarrhea. 
The  claims  are  made  for  them  that  they  do  not  act  in  the  stom- 
ach, but  liberate  the  tannic  acid  in  the  intestines.  Dose  of  each, 
10  grains  (0.7  gm.). 

Styptics. — The  astringent  remedies  especially  used  as  styptics, 
that  is,  to  check  hemorrhage,  are:  Solutions  of  epinephrine, 
antipyrine,  alum,  silver  nitrate,  ferric  chloride,  ferric  sulphate,  and 
ferric  subsulphate  (Monsell's  solution),  very  hot  water,  very  cold 
water,  glycerite  of  tannic  acid,  and  2  per  cent,  acetic  acid. 

ANTHELMINTICS 

An  anthelmintic  is  a  remedy  designed  to  promote  the  death  or 
expulsion  of  intestinal  worms.  Most  of  the  remedies  are  also 
toxic  to  man,  and  since  the  anthelmintic  is  to  attack  the  worm, 
rather  than  the  patient,  and  the  worms  are  just  as  likely  to  be 
adult  worms  when  they  occur  in  a  child  as  when  they  occur  in 
man,  the  age  rule  for  dosage  cannot  apply.  Hence  the  dose  must 
be  as  large  as  one  dare  risk,  whether  the  patient  is  a  child  or  an 
adult. 

Before  the  administration  of  a  toxic  anthelmintic  it  is  custom- 
ary to  starve  the  patient  for  from  twelve  to  twenty-four  hours 


108  PHARMACOLOGY  AND   THERAPEUTICS 

and  to  give  a  brisk  cathartic,  the  object  being  to  clean  out  the 
intestines  and  leave  the  worm  in  an  exposed  condition.  The 
dose  is  then  administered,  and  is  followed  in  four  or  five  hours  by 
a  brisk,  rapidly  acting  cathartic,  such  as  castor  oil  or  salts,  to 
carry  out  the  worm.  Castor  oil  has  been  objected  to  on  the 
ground  that  an  oily  medium  will  promote  the  absorption  of  the 
poison  by  the  patient.  This  may  be  true  if  rapid  evacuation  of 
the  bowels  does  not  take  place ;  but  castor  oil  and  its  soap  prod- 
ucts hurry  through  the  intestines  and  are  not  much  absorbed 
unless  catharsis  fails.  The  different  kinds  of  parasite  require 
different  kinds  of  treatment,  as  follows: 

i.  The  Pin-  or  Thread-worms  (Oxyuris  Vermicularis). — 
These  are  tiny,  thread-like  organisms  which  live  in  great  abun- 
dance in  the  colon  or  the  adjoining  portion  of  the  ileum,  chiefly 
in  the  mucus.  As  they  do  not  cling  to  the  intestinal  wall,  they 
are  readily  carried  out  by  cathartics;  or,  as  they  are  very 
vulnerable,  may  be  attacked  by  destructive  colon  irrigations  or 
enemata.  Occasionally  they  penetrate  the  mucous  membrane 
of  the  intestine  or  inhabit  the  appendix,  and  then  they  cannot  be 
dislodged. 

The  cathartics  mostly  employed  are  calomel  and  castor  oil. 
A  number  of  substances  are  used  for  colon  injection,  viz.,  the 
infusion  of  quassia,  lime-water,  a  solution  of  phenol,  0.25  per 
cent.,  a  solution  of  quinine  bisulphate,  1 12000,  a  solution  of  tannic 
acid  or  alum,  30  grains  (2  gm.)  in  one  pint  (480  c.c),  and  soap- 
suds containing  }4  ounce  of  the  oil  of  turpentine  to  a  quart. 
The  astringents  are  effective  not  only  by  shriveling  the  worms, 
but  also  by  lessening  the  intestinal  mucus  in  which  the  worms  may 
lodge.  The  Tania  nana,  which  are  tiny  tape-worms,  are  some- 
times taken  for  pin- worms. 

2.  The  Round- worms. — 1.  The  common  round- worm,  Ascaris 
lumbricoides,  grows  to  a  length  of  6  to  12  inches  or  even  more. 
They  usually  inhabit  the  small  intestine,  but  may  be  found  in 
the  colon  or  stomach,  and  have  even  been  known  to  stop  up  the 
common  bile-duct.  The  author  has  had  several  patients  who 
have  vomited  round- worms,  and  in  two  instances  drew  up  a  piece 
of  round-worm  through  a  stomach-tube.  These  must  have  been 
in  the  stomach.  They  may  be  the  cause  of  intestinal  hemorrhage. 
The  remedies  are: 

Santonin  (santoninum) ,  a  glucoside  from  santonica  (Levant 
wormseed),  dose,  2  grains  (0.12  gm.)  for  an  adult,  and  1  grain 
(0.06  gm.)  for  a  child  of  five  years.  The  ^-grain  (0.03  gm.) 
troches  are  official.  Santonica,  }4  dram  (2  gm.),  is  sometimes 
taken  as  it  is  or  in  the  form  of  an  infusion.  Santonin  is  highly 
toxic,  and  death  has  occurred  from  5  grains  (0.3  gm.)  in  an 


ANTHELMINTICS  IO9 

adult,  and  3  grains  (0.2  gm.)  in  a  child.  The  symptoms  of 
poisoning  are  nausea,  vomiting,  and  central  stimulation.  The 
reflexes  are  increased,  and  there  may  be  headache,  dizziness, 
delirium,  hallucinations,  and  possibly  epileptiform  convulsions, 
followed  by  collapse  and  death.  A  peculiarity  of  santonin 
poisoning  is  partial  blindness,  accompanied  by  yellow  vision. 
Baxter  reports  lost  vision  in  a  girl  of  five  after  y2  grain 
(0.03  gm.).  Jelliffe  (1906)  reports  prolonged  convulsions, 
followed  by  collapse,  in  a  girl,  from  two  troches  followed  by 
castor  oil  which  failed  to  move  the  bowels.  After  this  she  was 
blind,  very  restless,  and  prostrated  for  three  weeks,  and  showed 
signs  of  nephritis.     She  became  a  permanent  epileptic. 

The  treatment  of  poisoning  is  lavage  of  the  stomach,  followed 
by  a  large  dose  of  Epsom  salts,  the  inhalation  of  ether,  and  the 
management  of  symptoms  as  they  arise.  The  central  stimu- 
lation must  be  handled  with  care  because  of  the  tendency  to 
collapse. 

Santonin  has  come  into  notice  of  late  as  a  remedy  for  the  pains 
of  locomotor  ataxia  and  for  diabetes,  but  clinical  data  do  not 
justify  these  uses  of  so  dangerous  a  drug. 

Chenopodium  (American  wormseed)  is  sometimes  employed 
in  dose  of  15  grains  (1  gm.),  i.  e.,  about  half  a  level  teaspoon, 
and  its  volatile  oil  in  dose  of  3  minims  (0.2  c.c).  Its  toxicology 
is  that  of  the  volatile  oils. 

Spigelia  (pink-root)  has  an  official  fluidextract,  dose,  30  minims, 
(2  c.c).  It  is  frequently  given  with  senna  (fluidextract  of  pink- 
root  and  senna),  the  senna  furnishing  the  required,  though  rather 
late,  cathartic  action.  In  poisoning  it  causes  central  depression, 
with  prostration,  stupor  or  coma,  muscular  weakness,  incoordina- 
tion, and  collapse. 

2.  The  hookworms  {U urinaria  americana)  are  treated  by 
thymol,  30  grains  (2  gm.),  betanaphthol,  15-30  grains  (1-2 
gm.),  and  oleoresin  of  aspidium,  1  dram  (4  gm.),  and  by  enemata. 
Patterson,  of  Porto  Rico,  reports  that  thymol  is  best,  beta- 
naphthol is  next  best,  and  aspidium  is  useless.  Thymol  has  in 
several  instances  caused  fatal  poisoning  of  the  volatile  oil  type. 
Death  has  resulted  from  15  grains  (1  gm.)  in  a  child;  yet  in 
adults  as  much  as  225  grains  (15  gm.)  have  been  given  in  twelve 
hours  (Bozzolo,  191 2)  without  any  toxic  effects.  Public  Health 
Bulletin  No.  32  recommends  a  dose  of  Epsom  salts  at  night, 
followed  at  6  a.  m.  by  half  the  dose  of  thymol,  at  8  by  the  other 
half  of  the  thymol,  and  at  10  by  another  dose  of  Epsom  salts. 
This  treatment  is  repeated  once  a  week.  The  dose  recommended 
is  7K  grains  (0.5  gm.)  for  a  child  of  five  years,  and  45-60  grains 


IIO  PHARMACOLOGY  AND  THERAPEUTICS 

(3  to  4  gm.)  for  an  adult,  given  in  5-grain  (0.3  gm.)  capsules. 
Musgrave  recommends  thymol  for  irrigation  in  amebic  coli- 
tis. 

3.  The  tape-worms  seen  in  America  are  mostly  that  of  beef, 
Tcenia  saginata;  that  of  fish,  Tcenia  bothriocephalus ;  and  the 
dwarf  tape-worm,  Tcenia  nana.  The  remedies  are  sometimes 
called  teniacides  and  teniafuges.  The  favorite  remedy  is  oleo- 
resin  of  aspidium  (male-fern),  1  dram  (4  gm.)  in  capsules. 
Others  are  cusso,  1  dram  (4  gm.)  in  infusion;  granatum  (pome- 
granate root  bark),  2  drams  (8  gm.)  in  infusion;  pepo  (pumpkin- 
seed),  }4  ounce  (15  gm.)  in  infusion;  kamala,  1  dram  (4  gm.) 
mixed  with  syrup;  oil  of  turpentine,  }4  ounce  (15  c.c),  and 
chloroform,  1  dram  (4  c.c).  Pelletierinc,  an  alkaloid  from 
granatum,  in  the  form  of  the  tannate,  dose,  4  grains  (0.25  gm.), 
and  amorphous  filicic  acid,  one  of  the  constituents  of  male-fern, 
dose,  10  grains  (0.7  gm.),  are  also  employed.  Power  and  Sal- 
way  failed  to  find  any  anthelmintic  properties  in  the  constituents 
of  pumpkin-seed. 

Poisoning  by  aspidium,  granatum,  and  kamala  shows  in 
gastro-intestinal  irritation,  with  vomiting,  purging,  stupor, 
vertigo,  muscular  twitching,  collapse,  and  perhaps  irritation  of 
the  kidneys.  There  may  be  hemolysis  with  jaundice  (Grawitz). 
We  have  several  times  seen  severe  gastro-enteric  irritation  with 
vertigo  and  prostration  result  from  the  hospital  "Early-Bird" 
mixture.  This  consists  of  pumpkin-seed,  2  drams  (8  gm.), 
cusso  and  granatum,  each,  1  dram  (4  gm.),  made  into  an  infusion, 
to  which  are  added  kamala,  1  dram  (4  gm.),  oleoresin  of  aspidium, 
1  dram  (4  gm.),  glycerin,  y2  ounce  (15  c.c),  mucilage  of  acacia, 
y2  ounce  (15  c.c),  and  water  to  make  the  total  amount  8  ounces 
(240  c.c).  After  the  usual  preliminary  starvation,  this  quantity 
is  taken  in  two  drafts  two  hours  apart.  The  "early  bird "  usually 
gets  the  worm. 

CATHARTICS 

A  cathartic  is  a  measure  designed  to  promote  defecation. 
Such  a  remedy  may  be  employed — (1)  In  cases  of  constipation; 
(2)  for  the  removal  of  irritating  or  otherwise  harmful  material 
from  the  intestines,  as  in  food-poisoning,  intestinal  putrefaction, 
and  some  forms  of  diarrhea;  (3)  for  general  depletion,  as  in 
plethoric  or  dropsical  states,  cerebral  congestion,  etc. 

Constipation  is  a  condition  of  insufficient  frequency  of  de- 
fecation, or  of  insufficient  quantity  regardless  of  frequency,  or 
of  hardness  and  dryness  of  the  feces.  The  usual  number  of 
stools  in  a  day  is  one  or  two,  but  many  people  maintain  health 


CONSTIPATION 


III 


Muscle 


Aucrbochi 
"Plexus 


though  they  habitually  depart  from  this  rule  in  a  marked  degree. 
The  feces  are  normally  composed  of  food  residue,  bacteria,  secre- 
tions, and  products  of  chemic  and  bacterial  activities  in  the 
intestinal  canal.  In  some  cases  the  bacteria  form  as  much  as 
one- third  of  the  dried  feces  (Strasburger). 

Constipation  may  be  due — (i)  To  partial  organic  obstruc- 
tion; (2)  to  spasmodic  obstruction,  as  in  fissure  of  the  anus. 
hemorrhoids,  and  spastic  constipation;  (3)  to  deficient  motility 
of  the  intestinal  tract;  (4)  to  insufficiency  of  normal  stimuli; 
or  (5)  to  lack  of  sensitiveness  to  normal  stimuli.  Even  retarded 
emptying  of  the  stomach  may  be  a  cause  of  constipation,  the 
abnormal  prolongation  of  the  action  of  the  digestive  ferments 
in  the  stomach  resulting  in  a 
lessening  of  the  amount  of 
material  that  reaches  the  co- 
lon. 

Organic  obstruction  maybe 
caused  by  tumor  or  stricture 
of  the  intestine,  by  an  angu- 
lation or  kink,  either  congeni- 
tal or  the  result  of  adhesions, 
ptosis,  etc.,  or  by  pressure 
from  other  organs,  as  a  retro- 
verted  uterus  or  an  ovarian 
cyst.  Deficient  motility  may 
show —  (1)  By  diminished 
peristalsis  of  small  intestine, 
cecum  or    colon,  resulting  in 

retardation  in  the  passage  of  the  intestinal  contents,  or  (2)  by 
defect  in  the  expulsive  mechanisms  of  the  rectum,  resulting  in 
stagnation  and  over  accumulation  in  the  pelvic  colon  and  rec- 
tum. Insufficiency  of  normal  stimuli  may  result  from  acholia 
or  from  food  residue  that  is  either  insufficient  or  not  stimulat- 
ing. Insufficient  residue  may  result  from  eating  too  little  food 
or  too  digestible  food.  Lack  of  sensitiveness  to  stimuli  is  seen  in 
the  aged,  and  in  those  who  regularly  go  days  or  weeks  between 
stools. 

The  Mechanical  Factors  of  Defecation. — The  Small  In- 
testines.— The  peristaltic  wave  is  the  active  force  in  the  propul- 
sion onward  of  the  contents  of  the  small  intestine.  Its  stimulus 
depends  on  the  integrity  of  Auerbach's  plexus,  and  the  peristaltic 
movement  is  coordinated  and  purposeful.  It  involves  contrac- 
tion above  the  stimulating  object  and  relaxation  below  it.  The 
wave,  once  started,  is  propelled  from  muscle-fiber  to  muscle- 
hber,  directly  or  through  nerve-fibrils,  and  the  wave-like  rather 


Fig.  2. — Chart  showing  local  and 
central  innervation  of  the  small  intes- 
tine (after  Dixon). 


112  PHARMACOLOGY  AND    THERAPEUTICS 

than  continuous  contraction  is  insured  by  a  short  refractory 
period  of  the  muscle  (Magnus).  Under  abnormal  stimuli,  as 
by  irritant  cathartics,  the  normal,  slow,  worm-like  peristaltic 
movement  may  become  a  " peristaltic  rush"  (Meltzer  and  Auer), 
with  discharge  of  practically  the  whole  contents  of  the  small 
intestine  into  the  cecum  in  a  very  short  time.  It  is  probable  that 
the  site  of  constipation  is  rarely  in  the  small  intestines,  except 
possibly  in  the  neighborhood  of  the  ileocolic  junction. 

The  Cecum  and  Colon. — These  form  a  great  reservoir  along 
which  the  contents  are  passed  very  slowly,  and  probably  in  a 
manner  different  from  that  in  the  small  intestines.  In  the 
cecum  and  ascending  colon  so  much  liquid  is  absorbed  that  by  the 
time  the  residue  reaches  the  transverse  colon  it  has  begun  to 
take  on  the  consistence  of  feces  (Roith).  Regular  antiperistalsis 
has  been  observed  in  cats  and  other  animals;  and,  as  shown  by 
the  x-rays  in  man,  it  takes  but  a  few  moments  for  a  rectal  in- 
jection to  reach  the  cecum. 

The  time  normally  required  for  the  passage  from  stomach  to 
rectum  has  been  studied  under  the  x-ray  by  meals  mixed  with 
bismuth  salts.  For  the  first  portion  of  a  bismuth  meal  to  reach 
the  cecum  Hertz  found  the  average  time  to  be  four  and  a  half 
hours,  and  for  the  last  portion  nine  hours.  Satterlee  and  LeWald, 
in  27  cases,  found  two  hours  the  average  time  for  the  food  to 
reach  the  cecum,  only  one  hour  being  required  in  three  cases, 
and  the  longest  tirrie  being  live  hours.  In  9  cases  it  took  from 
four  to  seven  hours  for  complete  emptying  of  the  small  intestine. 
Hertz  found  that  the  hepatic  flexure  is  reached  in  six  and  a  half 
hours,  the  splenic  flexure  in  nine  hours,  the  iliac  colon  in  eleven 
hours,  the  pelvic  colon  in  twelve  hours,  and  the  lower  part  of 
the  pelvic  colon  in  eighteen  hours.  At  this  point  is  the  pelvi- 
rectal reservoir  in  which  the  contents  remain  until  defecation. 

On  arising  in  the  morning  or  on  eating  breakfast,  as  observed 
by  Hertz  with  the  x-rays,  peristalsis  begins  in  the  colon  and  car- 
ries the  feces  into  the  rectum.  When  the  rectum  becomes  dis- 
tended, the  subject  receives  subjective  sensations  of  a  desire  to 
go  to  stool.  At  stool  the  abdominal  muscles  are  contracted  so 
that  more  material  is  forced  into  the  rectum  and  into  the  anal 
canal.  This  results  in  the  defecation  reflex,  with  relaxation  of 
the  anal  sphincters,  colon  peristalsis,  and  renewed  contraction  of 
the  abdominal  muscles.  At  stool  the  whole  large  intestine  from 
splenic  flexure  onward  is  emptied,  a  relatively  long  column  of 
feces  resulting.  In  addition,  while  the  act  of  defecation  is  taking 
place,  a  portion  of  the  contents  of  the  transverse  colon  may  move 
into  the  descending  colon  and  pass  out.  The  shape  and  the  size 
of  feces  as  passed  are  largely  determined  by  their  consistence  and 


CATHARTIC   MEASURES  113 

by  the  irritability  of  the  anal  canal,  and  not  by  strictures  high  up 
in  the  rectum.       y 

According  to  the  above,  the  stool  normally  contains  the  food- 
products  which  have  reached  the  splenic  flexure.  Hence  the 
first  portions  of  a  meal  eaten  nine  or  ten  hours  before  will  normally 
appear  in  the  stool,  while  a  portion  of  the  residue  from  that  meal 
will  not  appear  until  the  next  stool.  If  there  is  but  one  stool  a 
day,  therefore,  it  will  normally  contain  material  from  the  food 
eaten  as  much  as  thirty-four  hours  before.  Hence,  Hertz  con- 
cludes that  if,  after  a  morning  defecation,  the  residue  of  food 
taken  at  4  p.  m.  does  not  appear  in  the  feces  the  second  morning 
after,  there  is  constipation.  To  check  off  the  material  of  a  given 
meal,  it  is  customary  to  give  a  capsule  of  5  grains  (0.3  gm.)  of 
carmine,  or  half  a  dozen  lozenges  of  charcoal,  about  30  grains 
(2  gm.),  with  the  meal.  These  color  the  feces  from  that  meal 
pink  or  gray-black  respectively.  (Excellent  reference  works  on 
the  actions  of  the  bowels  are:  Hertz,  "Constipation  and  Allied 
Intestinal  Disorders,"  1909;  W.B.Cannon,  "The  Mechanical 
Factors  of  Digestion,"  191 1.) 

Griping  or  cramp  is  a  condition  often  produced  by  cathartics. 
It  is  caused  by  overactivity  of  the  intestinal  muscles,  as  from 
overstimulation  or  from  attempts  to  overcome  obstruction.  The 
work  of  Hertz  suggests  that  the  distention  behind  the  contracted 
ring  may  be  the  cause  of  the  pain. 

CATHARTIC  MEASURES 

Cathartic  measures  are  laxative  when  employed  to  produce 
soft  stools  of  about  normal  frequency,  and  purgative  when  em- 
ployed to  produce  copious  soft  or  liquid  movements.  A  hydra- 
go  gue  is  any  remedy  that  will  result  in  copious  watery  stools. 
The  term  aperient  is  sometimes  employed  for  any  cathartic,  but 
especially  for  a  saline. 

The  term  cholagogue  was  formerly  applied  to  certain  sub- 
stances which  were  thought  to  increase  the  production  of  bile. 
The  amount  of  bile  may  be  increased  by  large  amounts  of  ox-gall 
or  bile-salts  administered  by  mouth,  and  to  a  slight  extent  by 
salicylic  acid.  It  is  also  increased  by  the  injection  of  secretin 
into  the  blood  (Starling) .  But  pharmacologic  research  has  shown 
that  we  have  no  effective  agents  which,  in  therapeutic  amounts, 
have  this  action,  so  the  term  had  best  be  abandoned. 

Cathartic  measures  include  habit  formation,  response  to  the 
desire  to  defecate,  exercise,  massage,  food,  and  drugs. 

1.  Habit  formation  is  the  establishment  of  a  regular  time  for 
the  daily  stool.  Usually  this  time  is  just  after  breakfast,  both 
because  this  is  a  convenient  time  and  because  the  activity  of 
8 


114  PHARMACOLOGY  AND  THERAPEUTICS 

dressing  and  the  taking  of  food  both  tend  to  stimulate  colon 
peristalsis.  Even  when  there  is  no  desire  to  defecate  it  is  ad- 
visable to  make  the  attempt,  for  the  voluntary  effort  may  force 
some  feces  into  the  rectum  and  so  result  in  the  proper  subjective 
sensations  which  bring  about  the  defecation  reflexes.  The  after- 
breakfast  smoke  tends  to  promote  defecation. 

2.  That  response  to  the  desire  to  defecate  is  important  is  indi- 
cated by  Hertz's  observation  that  the  rectum  accommodates 
itself  to  the  presence  of  a  fecal  accumulation,  so  that  if  the  desire 
is  not  responded  to,  it  will  pass  away  and  the  defecation  reflex 
become  impaired.  Many  persons  have  become  habitually  con- 
stipated because  their  occupation  interferes  with  defecation. 
Women  in  business,  for  example,  often  suppress  the  desire  to 
defecate  rather  than  pass  a  number  of  men  to  reach  the  toilet. 

3.  The  exercises  of  value  are:  walking,  running,  rowing, 
horseback  riding,  tennis,  golf,  gymnastics,  and  special  abdominal 
exercises.  Such  are  bending  the  body  forward  or  backward, 
or  from  side  to  side;  lying  on  the  back  and  raising  the  legs  to  a 
right  angle  with  the  trunk,  or  raising  the  trunk  to  a  right  angle 
with  the  legs,  etc.  It  must  be  noted  that  there  are  many  persons 
who  live  a  very  sedentary  life  yet  are  not  constipated. 

4.  Massage  may  be  either  superficial  or  deep.  It  may  be 
performed  by  active  kneading  in  the  direction  of  the  colon,  by  a 
rotary  motion  of  the  abdominal  wall  over  the  viscera,  or  by 
rolling  a  cannon-ball  or  ball  of  clay  covered  with  leather  or 
chamois  over  the  abdomen  from  cecum  to  sigmoid  below  the 
navel  in  the  direction  of  the  hands  of  a  clock.  Such  a  clay  ball 
may  be  heated. 

5.  Foods  and  Drugs. — There  is  no  sharp  dividing-line  between 
these,  certain  substances  acting  as  food  or  as  drug  according 
to  circumstances.  A  substance  cannot  serve  as  nutriment  and 
act  as  a  cathartic  at  the  time  same;  for  if  it  is  absorbed,  it  does 
not  act  as  a  cathartic,  and  vice  versa. 

Foods  tend  to  promote  bowel  movements  by — (1)  Chemic 
stimulation,  as  of  sugars,  and  fruit  acids  and  their  salts;  and  di- 
gestive products,  such  as  proteins,  amino-acids,  soaps,  etc. ;  (2)  me- 
chanical stimulation,  as  by  seeds  or  husks;  (3)  increasing  the 
bulk  of  intestinal  contents,  as  by  cellulose,  skins,  etc.,  and  un- 
absorbed  oils  and  fats  or  their  soaps. 

Foods  of  too  ready  digestibility  are  constipating.  Of  enor- 
mous importance  (Hertz)  is  cellulose;  in  fact,  Rubner  states  that 
"in  the  absence  of  cellulose  from  food  almost  everything  is  ab- 
sorbed." Fruits  and  vegetables  rich  in  cellulose  pass  into  the 
intestines  as  paste  and  stimulate  peristalsis;  meat,  eggs,  and 
milk  pass  as  liquids  and  so  favor  segmentation,  but  not  peristalsis 


CATHARTIC   MEASURES  115 

(Cohnheim).  Hertz  reports  that  of  the  dry  substance  of  meat, 
eggs,  white  bread,  and  rice,  only  5  per  cent,  appeared  in  the  feces; 
while  of  the  dry  substance  of  green  vegetables  and  brown  bread 
15  per  cent.,  and  of  the  dry  substance  of  carrots  and  turnips  20 
per  cent.,  appeared  in  the  feces.  The  feces  of  a  mixed  diet  gave 
100  gm.  of  water  and  35  gm.  of  dry  substance;  the  feces  of  a 
vegetable  diet  gave  260  gm.  of  water  and  75  gm.  of  dry  substance. 

Vegetables  and  salads  mostly  contain  fibrous  tissue  and  cellu- 
lose. Many  vegetables  are  as  much  laxative  as  nutritive.  Salad 
dressing  contains  oil,  which  tends  to  be  laxative. 

Cereals  contain  cellulose.  Oatmeal  is  especially  laxative, 
because  of  the  presence  of  indigestible  husks.  Oatmeal  water  is 
even  said  to  be  more  laxative  than  waters  made  from  other  cereals, 
but  no  soluble  laxative  principle  has  been  isolated,  and  the  water 
lacks  the  laxative  agent  (the  husks)  of  the  oatmeal  itself. 

Fruits  contain  sugar,  cathartic  acids  or  salts,  indigestible 
structural  parts  (fiber,  cellulose,  skins,  etc.),  seeds,  and  non- 
absorbable colloid  pectin  bodies.  Those  most  frequently  con- 
sidered laxative  are  prunes,  figs,  and  dates;  but  an  apple,  an 
orange,  a  banana,  or  some  grapes  at  bedtime  will  often  insure 
the  morning  stool.     The  morning  coffee  also  promotes  defecation. 

Agar-agar  is  a  form  of  hemi-cellulose  prepared  from  several 
species  of  seaweed.  It  has  the  property  of  absorbing  water  to 
form  a  jelly-like  material.  After  heating  1.5  parts  of  it  with  100 
of  water  it  cools  to  a  stiff  jelly,  which  is  used  extensively  in 
bacteriology  as  a  culture-medium.  It  is  ordinarily  unaffected 
by  the  digestive  fluids,  and  is  not  absorbed  from  the  alimentary 
tract,  hence  is  not  a  food.  But  it  absorbs  water  and  swells, 
thus  serving  the  double  purpose  of  carrying  water  down  into  the 
intestines  and  of  increasing  the  bulk  of  the  colon  contents. 

Its  disadvantages  are :  (1)  It  is  an  excellent  culture-medium 
and  may  favor  the  development  of  intestinal  bacteria,  itself 
becoming  decomposed;  (2)  it  mechanically  retards  the  absorp- 
tion of  food-products;  and  (3)  by  acting  as  a  demulcent  it  lessens 
the  normal  stimulation  of  the  intestine  by  the  food  materials. 
To  overcome  this  last  disadvantage  Schmidt  has  recommended 
the  addition  of  cascara,  and  such  a  preparation  is  on  the  market 
under  the  name  of  regulin.  This  is  slightly  bitterish  from  the 
cascara,  the  amount  of  which  is  not  stated.  A  teaspoonful  to  a 
tablespoonful  may  be  taken  at  night,  or  night  and  morning, 
dry  or  with  water,  or  with  the  morning  cereal.  Its  laxative 
action  is  frequently  delayed  for  several  days;  but  after  that  the 
patient  may  continue  having  a  soft  daily  stool  so  long  as  the 
regulin  is  taken.  Another  laxative  combination  with  agar  is 
phenolphthalein-agar,  of  which  one  level  teaspoonful,  weighing 


Il6  PHARMACOLOGY  AND    THERAPEUTICS 

15  grains  (1  gm.),  contains  y2  grain  (0.03  gm.)  of  phenolphthale'in. 
(Pararegulin  is  liquid  paraffin  with  the  addition  of  a  small 
amount  of  cascara.     It  is  practically  non-absorbable.) 

Whole  flaxseed  and  psyllium  seeds  are  sometimes  taken  in 
teaspoonful  dose  to  increase  the  bulk  of  the  feces.  Their  muci- 
laginous coat  absorbs  water  and  swells. 

Drugs. — These  are  usually  administered  by  mouth,  but  a 
few  may  be  employed  subcutaneously,  and  some  are  used  by 
rectum  in  the  form  of  enemata  and  suppositories.  Cathartic 
drugs  may  be  loosely  classified  as: 

A.  Those  acting  by  a  selective  affinity  for  the  nervous 
structures. 

B.  Those  acting  as  local  irritants. 

C.  The  saline  cathartics,  which  have  a  special  action. 

Cathartics  Acting  by  Selective  Affinity 
In  Class  A  we  have:  Physostigmine,  dose,  ^V  grain  (0.001 
gm.),  which  stimulates  the  ends  of  the  vagus  or  motor  nerves  of 
the  intestines;  and  apocodeine,  dose,  y2  grain  (0.03  gm.),  which 
depresses  the  ends  of  the  splanchnic  or  inhibitory  nerves,  thus 
freeing  the  bowel  from  inhibition  and  increasing  its  motor 
activity. 

THE  IRRITANTS 
In  Class  B,  the  irritants,  we  have  a  large  and  valued  list  of 
cathartics,  and  these  may  be  subdivided  for  convenience  of  study 
into  several  small  groups.     These  are: 

(a)  Some  very  weak  laxatives. 

(b)  The  fixed  oils  and  their  products  (soap  and  glycerin). 

(c)  The  mercurials. 

(d)  The  anthracene  derivatives. 

(e)  Acids,  resins,  and  glucosides  with  drastic  action — the 
drastics. 

(a)  VERY  WEAK  LAXATIVES 

The  very  weak  laxatives  include  certain  drugs  which  do  not 
have  a  greater  than  laxative  effect,  even  in  quite  large  amounts. 
Of  special  interest  are  manna,  sulphur,  liquid  paraffin,  and  the 
bile  salts. 

Manna  depends  for  its  action  on  mannite,  a  peculiar  sugar 
that  is  not  readily  absorbed.  It  enters  into  the  compound  in- 
fusion of  senna. 

Sulphur  increases  the  bulk  of  the  feces  and  makes  the  stool 
soft.  It  is  partly  changed  by  the  proteins  of  the  alimentary 
tract  into  sulphides,  sulphites,  and  sulphates,  which  are  mildly 
stimulating  to  peristalsis.     The  intestinal  gases  are  increased 


VERY   WEAK   LAXATIVES  117 

in  their  sulphureted  hydrogen  constituent,  and  the  feces  may 
have  a  sulphuret  odor.  Some  of  the  products  are  absorbed,  as 
shown  by  the  increase  of  sulphates  in  the  urine. 

Sulphur,  cream  of  tartar  (potassium  bitartrate),  and  molasses 
is  a  favorite  household  "spring  medicine,"  and  tablets  may  be 
had  containing  various  proportions  of  cream  of  tartar  and  sul- 
phur. For  the  blood,  in  acne,  it  is  given  in  the  form  of  calcium 
sulphide  (calx  sulphurata) ,  dose,  i  grain  (0.06  gm.).  Precipitated 
sulphur  and  potassa  sulphurata  are  also  used  in  lotions  for  acne. 
In  scabies  it  is  sprinkled  in  the  bed,  and  also  applied  to  the  skin 
in  ointment  form.  For  room  disinfection  it  is  burned  to  produce 
sulphur  dioxide  (SO?). 

There  are  three  official  forms  of  sulphur,  viz. : 

Sulphur  sublimatum  (sublimed  sulphur,  flowers  of  sulphur), 
which  is  preferred  as  a  laxative,  as  it  contains  free  sulphurous 
acid  and  is  gritty. 

Sulphur  lotum  (washed  sulphur),  which  is  freed  from  acid 
by  washing  with  ammonia,  but  is  gritty.  Its  15  per  cent,  oint- 
ment (unguentum  sulphuris)  is  official. 

Sulphur  prazcipitatum  (precipitated  sulphur),  prepared  by 
precipitation  from  a  solution  of  alkaline  sulphide.  It  is  soft  and 
not  gritty,  and  is  preferred  in  lotions. 

Liquid  Paraffin. — This  petroleum  oil,  known  also  as  liquid 
vaseline,  liquid  albolene,  Russian  mineral  oil,  and  liquid  petrola- 
tum, has  come  into  extensive  use,  at  the  suggestion  of  Sir  Arbuth- 
not  Lane,  for  chronic  intestinal  stasis  with  auto-intoxication. 
It  is  not  absorbed  from  the  alimentary  tract  (Bradley,  1911, 
Bloor,  1913),  hence  serves  to  soften  and  to  increase  the  bulk 
of  the  feces.  It  may  exert  an  antiseptic  effect  on  some  of  the 
strains  of  fecal  bacteria,  but  this  has  not  been  demonstrated.  It 
has  little  effect  in  the  stomach,  except  that,  like  other  oils,  it 
tends  to  retard  stomach  emptying  and  gastric  digestion.  It  is 
only  mildly  laxative,  and  frequently  must  be  given  with  some 
stronger  laxative,  such  as  cascara.  The  dose  is  1  ounce  (30  c.c.) 
two  or  three  times  a  day,  the  refined  varieties  being  almost  taste- 
less and  readily  taken.     If  desired,  aromatics  may  be  added. 

Bile  Salts. — The  bile  salts  are  sodium  glycocholate  and  sodium 
taurocholate.  They  hold  lecithin  and  cholesterin  in  solution  in 
the  bile,  and  serve  as  carriers  of  fats  and  soaps  and  their  products 
into  the  villi  of  the  intestine.  They  are  then  reabsorbed  by  the 
capillaries  and  returned  to  the  liver  by  the  portal  vein.  Owing 
to  their  ready  excretion  by  the  liver  cells  they  act  to 
increase  the  quantity  of  bile.  In  human  bile  from  a  biliary 
fistula  Rosenbloom  found  1.01  per  cent,  of  total  bile  salts,  and 
Yeo  and  Herroun  found  sodium  taurocholate,  0.055  Per  cent-, 


Il8  PHARMACOLOGY  AND  THERAPEUTICS 

and  sodium  glycocholate,  0.165  per  cent.  In  human  bile  from 
the  gall-bladder  Hoppe-Seyler  found  0.87  per  cent,  of  the  tauro- 
cholate  and  3.03  per  cent,  of  the  glycocholate.  Fresh  ox-gall 
contains  about  3  per  cent,  of  the  salts,  but  is  variable  in  its 
composition.  Dried  ox-gall  and  mixtures  of  the  salts  are  on  the 
market.  The  salts  are  recommended  in  dose  of  5  grains  (0.3  gm.) 
to  promote  the  production  of  bile,  to  promote  the  absorption  of 
fats,  and  to  enhance  the  action  of  the  anthracene  cathartics. 
They  are  contraindicated  in  obstructive  jaundice. 

(b)  THE  FIXED  OILS,  SOAPS,  AND  GLYCERIN 

1.  Olive  oil  (oleum  olivae)  is  essentially  a  nutritive  and  di- 
gestible fat.  However,  in  amounts  of  one  or  two  tablespoonfuls 
it  may  have  a  mildly  laxative  action,  being  changed  to  soap  and 
glycerin  in  the  intestine.  In  large  amounts,  as  ]/2  pint  (240  c.c), 
it  is  only  partly  saponified,  and  gets  some  of  its  laxative  power 
from  increasing  the  bulk  of  the  intestinal  contents.  It  had  at  one 
time  a  reputation  for  the  cure  of  cholelithiasis;  but  as  a  solvent 
for  gall-stones  in  the  gall-bladder  it  has  no  value  whatever.  In 
the  larger  amounts  it  tends  to  form  soap-lumps  which  have  not 
infrequently  been  mistaken  for  gall-stones  in  the  feces.  It  dis- 
tinctly prolongs  the  emptying  time  of  the  stomach. 

Olive  oil  is  also  used  as  a  demulcent  to  diminish  excessive 
hydrochloric-acid  secretion  in  the  stomach,  especially  in  ulcer, 
and  to  allay  irritation  in  the  rectum.  Warm  oil  is  often  em- 
ployed by  rectum  to  soften  hard  feces,  but  Hertz  found  that  oil 
does  not  penetrate  the  lumps  of  feces,  and  that  these  are 
much  more  readily  softened  by  water. 

2.  Castile  soap  (sapo)  is  nearly  pure  sodium  oleate.  It  is 
mildly  irritant  to  mucous  membranes,  hence  is  laxative.  Soap- 
suds enemata  may  be  made  of  Castile  soap,  or  if  a  stronger  action 
is  desired,  of  laundry  soap,  which  contains  free  alkali  and  is  more 
irritating. 

3.  Glycerin  (glycerinum) ,  though  slightly  laxative  when  ad- 
ministered by  mouth,  is  chiefly  used  in  the  form  of  the  glycerin 
suppository  (suppositorium  glycerini),  or  as  a  mildly  irritating 
addition  to  an  ordinary  enema.  Hertz  says  it  is  irritant  to  the 
mucous  membrane  of  the  anal  canal,  but  not  to  that  of  the 
rectum. 

4.  Castor  Oil  (Oleum  Ricinf). — This  oil  is  saponified  in  the 
small  intestines  to  form  glycerin  and  sodium  ricinoleate,  a  soap 
which  is  much  more  irritant  than  Castile  soap  to  the  intestinal 
mucous  membrane.  Its  great  advantages  are  its  rapidity  of 
action,  its  thoroughness,  and  its  comparative  freedom  from 
irritative  griping,     After  a  dose  of  %-\  ounce  (15-30  c.c.)  it 


Fig.  3. — The  abdomen  of  this  patient  was  greatly  distended  with  gas,  which 
seemed  as  if  in  his  stomach,  though  unrelieved  by  belching.  After  a  rectal  injection 
of  bismuth  this  .v-ray  picture  was  taken,  the  patient  being  in  the  standing  position. 
The  light  areas  in  the  bowel  are  gas. 


Fig.  4. — The  same  patient  as  in  Fig.  3.  This  .r-ray  picture  was  taken  after 
free  movements  of  the  bowels  by  castor  oil.  There  was  complete  relief  from 
flatulency. 


THE   FIXED    OILS,    SOAPS,    AND    GLYCERIN  119 

usually  produces  one  or  more  copious  soft  or  watery  stools  in 
from  two  to  six  hours.  In  some  of  our  cases  over  a  quart  of  stool 
was  recovered  after  one  ounce  of  castor  oil.  It  has  little,  if 
any,  tendency  to  produce  inflammation,  hence  is  not  a  drastic 
cathartic;  but  it  is  a  powerful  stimulant  of  peristalsis.  This 
effect  is  dependent  on  the  formation  of  the  soap,  for  castor  oil 
unsaponified  is  bland  and  non-irritant.  If  used  by  rectum,  it 
should  be  saponified  with  an  alkali,  otherwise  it  acts  like  olive 
oil.  In  Rowntree's  experiments,  25  c.c.  by  hypodermatoclysis 
had  no  effect  upon  the  bowels,  and  merely  caused  a  painful 
swelling  at  the  site  of  the  injection. 

Administration. — Various  methods  of  administration  to  hide 
the  nauseating  taste  have  been  devised.  The  three-layer  method, 
in  which  the  oil  is  suspended  between  two  layers  of  flavored 
watery  or  alcoholic  liquid,  is  the  favorite.  For  this  purpose 
compound  tincture  of  cardamom,  spirit  of  peppermint,  whisky, 
orange-juice,  lemon-juice,  lemonade,  or  beer  may  be  employed. 
Glycerin  is  sometimes  used  for  the  lower  layer.  The  layers  should 
not  be  stirred  together.  The  favorite  drug-store  method  is  to  place 
some  syrup  of  sarsaparilla  in  a  glass  and  cause  it  to  foam  by 
carbonic  water  from  the  soda  fountain,  or  by  a  little  tartaric 
acid  and  sodium  bicarbonate.  Then  the  oil  is  poured  in  without 
allowing  any  to  get  on  the  edge  of  the  tumbler.  The  mixture 
must  not  be  stirred.  The  oil  floats  between  some  of  the  syrup 
below  and  the  foam  above,  and  the  whole  is  drunk  without 
stopping.  The  oil  is  not  tasted  at  all.  The  principle  of  these 
methods  is  to  have  the  mouth  and  tongue  wetted  with  a  pleasant 
flavored  liquid  (the  top  layer),  upon  which  the  oil  will  readily 
slip  down.  If  any  oil  sticks  to  the  tongue,  the  taste  will  be  per- 
ceived. For  infants  and  children,  an  emulsion  made  with  acacia 
and  a  flavored  syrup  may  be  employed.  There  are  some  pow- 
dered castor  oils  on  the  market,  such  as  risiccol  and  castor-lax, 
made  by  absorbing  castor  oil  with  magnesia.  To  get  a  full 
castor-oil  action  they  must  be  taken  in  very  large  dose,  2  ounces 
(60  gm.). 

Therapeutics. — Castor  oil  is  extensively  employed  in  dose  of  1 
ounce  (30  c.c.)  as  an  occasional  brisk  cathartic  for  the  thorough 
cleansing  of  the  intestines.  This  may  be  desired  in  fermentative 
diarrhea,  food  or  ptomain-poisoning,  intestinal  flatulency,  or  mu- 
cous colitis,  or  because  of  continued  colonic  stasis.  Such  thorough 
catharsis  is  prone  to  be  followed  by  constipation  for  a  day  or  two 
during  the  refilling  of  the  stagnant  bowel.  Castor  oil  in  cathartic 
amounts  is  not  suited  for  daily  or  very  frequent  repetition.  By 
its  activity  it  tends  to  congest  and  stimulate  the  female  pelvic 
organs,  hence  must  not  be  employed  as  a  cathartic  during  men- 


120  PHARMACOLOGY  AND    THERAPEUTICS 

struation  or  pregnancy,  though  it  is  sometimes  administered  to 
bring  on  labor  pains  at  full  term.  In  colitis  and  intestinal  putre- 
faction a  favorite  treatment  is  a  capsule  containing  2^2  minims 
(0.15  c.c.)  of  castor  oil  and  2^  grains  (0.15  gm.)  of  salol,  or 
twice  these  amounts,  three  or  four  times  a  day.  The  effect  of 
such  small  amounts  of  the  oil  is  problematic. 

(c)  THE  CATHARTIC  MERCURIALS 

Calomel  (hydrargyri  chloridum  mite),  the  mild  chloride 
of  mercury,  Hg2Cl2,  is  a  bland  or  unirritating  heavy  powder, 
completely  insoluble  in  water.  It  has  few  chemic  affinities, 
but  is  decomposed  by  alkalies.  When  it  is  added  to  a  solu- 
tion of  sodium  carbonate,  it  turns  gray  with  the  formation 
of  the  carbonate,  oxide,  or  hydroxide  of  mercury,  a  change 
which  presumably  takes  place  when  the  calomel  passes  from 
the  stomach  into  the  duodenum.  Some  of  the  salt  goes  into 
solution,  for  the  filtrate  contains  mercury  (MacCallum).  This 
gray  salt  of  mercury  has  more  chemic  affinities  than  calomel, 
is  irritant  locally,  and  is  antiseptic,  and  it  is  upon  this  chemic 
change  that  the  value  of  calomel  in  the  alimentary  tract  largely 
depends.  This  suggests  the  advisability  of  dividing  the  large 
doses,  so  that  not  too  much  is  passed  into  the  duodenum  at  one 
time. 

The  result  of  the  irritation  is  increased  peristalsis  beginning 
in  the  duodenum  and  extending  through  the  whole  length  of  the 
bowel.  In  addition  there  is  a  mild  antiseptic  action,  though 
many  more  bacteria  are  carried  out  by  good  catharsis  than  can 
be  killed  by  an  antiseptic.  Calomel  is  not  a  very  powerful  colon 
stimulant,  so  if  the  dose  is  too  small,  the  movement  may  not  be 
copious;  however,  if  the  dose  is  too  large,  there  may  be  griping, 
rectal  irritation  and  tenesmus,  and  numerous  small  stools. 

At  times,  if  the  action  is  not  severe  enough,  the  bowels  are  not 
thoroughly  cleaned  out,  and  the  result  is  autointoxic  headache 
and  lassitude.  The  explanation  of  this  is  that  the  calomel  hastens 
the  undigested  food  through  the  small  intestine  to  the  colon, 
where  the  putrefactive  bacteria  are  located.  The  raw  proteins, 
not  being  carried  out,  furnish  pabulum  from  which  these  bacteria 
generate  an  extra  amount  of  poisons  of  the  indol  type  (Herter). 
Because  of  this  not  infrequent  sequence  to  calomel,  it  is  the  cus- 
tom to  follow  the  dose  in  about  eight  hours  with  a  saline  cathartic 
to  insure  a  thorough  washing  out  of  the  colon. 

The  calomel  stools  may  be  gray  in  color  from  the  presence  of 
the  mercurous  oxide  or  other  mercurous  salts;  occasionally  they 
are  green  from  the  presence  of  unchanged  biliverdin,  this  being 
due  either  to  the  rapid  carrying  of  the  bile  through  the  intestines, 


THE   CATHARTIC   MERCURIALS  121 

or  to  the  prevention  of  the  usual  reduction  of  the  bile-pigment. 
This  prevention  may  result — (i)  From  the  direct  chemic  action 
of  the  mercury  salt  on  the  pigment;  (2)  from  an  antiseptic  effect 
upon  the  bacteria  which  cause  the  changes  in  bile-pigment,  or 
(3)  from  an  interference  with  the  oxidases.  Calomel  has  no 
effect  upon  the  secretory  power  of  the  liver,  but  the  increased 
activity  of  the  duodenum  may  favor  the  outflow  of  stored  bile 
from  the  gall-bladder. 

Calomel  may  be  given  in  the  form  of  a  powder  or  tablet 
triturate  (compressed  tablets  and  pills  are  not  recommended, 
as  the  calomel  is  insoluble),  in  amounts  of  1-3  grains  (0.06-0.2 
gm.)  in  divided  doses,  say  y±  grain  (0.015  gm.)  every  fifteen 
minutes  for  6  doses.  If  the  stomach  is  irritable,  even  smaller 
amounts  may  be  given  at  a  time.  It  is  quite  a  common  practice 
to  give  tablets  of  TV  grain  (0.006  gm.)  each  until  1  or  2  grains  have 
been  taken;  but  this  requires  too  many  doses  to  be  watched, 
and  spreads  the  dosage  over  too  long  a  time. 

At  one  time  it  was  taught  that  calomel  should  be  given  with 
sodium  bicarbonate  to  prevent  the  hydrochloric  acid  in  the  stom- 
ach from  changing  it  to  the  poisonous  and  corrosive  bichloride. 
But  it  has  been  shown  that  even  in  highly  acid  gastric  juice  the 
calomel  does  not  change  to  bichloride,  and  it  is  obvious  that  a 
few  grains  of  sodium  bicarbonate  could  have  little,  if  any,  effect 
in  neutralizing  the  acid  of  the  gastric  juice  during  the  whole 
time  the  calomel  remains  in  the  stomach.  If  the  stomach  needs 
sodium  bicarbonate,  the  patient  may  feel  better  after  such  a  dose, 
but  he  is  not  protected  from  poisoning.  The  administration  of 
acids  with  calomel  is  not  contraindicated. 

Therapeutics. — The  chief  uses  of  calomel  as  a  cathartic  de- 
pend upon  its  combined  cathartic  and  antiseptic  powers.  It  is 
employed : 

1.  At  the  onset  or  during  the  course  of  acute  illnesses. 

2.  In  plethoric  conditions,  such  as  are  usually  associated  with 
habitual  overeating  (so-called  "sluggish  liver"). 

3.  In  intestinal  auto-intoxication,  whether  associated  with 
liver  insufficiency  or  not,  and  in  food  or  ptomain-poisoning. 

4.  In  fermentative  conditions  of  stomach  and  bowels. 

5.  In  hyperacidity  and  "biliousness." 

Each  compound  cathartic  pill  contains  about  one  grain  of 
calomel.  The  other  mercurial  cathartics  are  the  mercury  or 
blue  pill  (massa  hydrargyri),  dose,  5  grains  (0.3  gm.);  and  the 
mercury  with  chalk  (hydrargyrum  cum  creta),  dose,  5  grains 
(0.3  gm.),  in  both  of  which  metallic  mercury  is  in  a  state  of  fine 
subdivision.  The  Pharmacopoeia  requires  that  these  prepara- 
tions shall  not  contain  more  than  traces  of  the  mercury  oxides. 


122  PHARMACOLOGY  AND  THERAPEUTICS 

Metallic  mercury  in  bulk,  when  administered  by  mouth,  may  act 
mechanically,  passing  out  of  the  intestines  unchanged;  but 
poisoning  has  occurred  from  its  ingestion. 

Mercurials  used  for  other  purposes  are  occasionally  cathartic, 
e.  g.,  the  protoiodide  given  for  syphilis;  in  such  cases  bismuth  or 
opium  is  sometimes  administered  with  them. 

(d)  THE  ANTHRACENE  DERIVATIVES 
The  drugs  of  this  class  are  the  chemicals,  phenolphthaleiin 
and  other  phthale'ins,  and  the  vegetable  drugs,  aloes,  frangula, 
cascara,  rhubarb,  and  senna.  These  depend  for  their  activity 
upon  a  resinous  body,  emodin  (trioxymethylanthraquinone) , 
and  cathartinic  acid,  or  upon  close  relatives  of  these.  Tschirch 
and  Heppe  report  2.6  per  cent,  of  emodin  in  frangula,  and  0.61 
per  cent,  in  cascara;.  but  Stewart  reports  about  1.5  per  cent, 
in  each.  In  rhubarb  there  is  1.5,  in  senna,  1,  and  in  aloes,  0.8 
per  cent.  These  principles  are  rather  readily  absorbed,  so  that 
the  crude  drugs  or  their  galenic  preparations  are  believed  to  be 
more  energetic  as  cathartics  than  the  separated  principles.  Their 
action  tends  to  be  enhanced  by  administration  with  an  alkali. 
In  the  case  of  phenolphthale'in,  it  has  been  shown  by  Wood  that 
in  the  presence  of  acid,  fermenting  intestinal  contents  there  may 
be  no  cathartic  effect.  As  a  rule,  they  do  not  act  so  well,  or  may 
fail  to  act,  in  the  absence  of  bile;  but  usually  in  such  cases  they 
can  be  made  active  by  the  addition  of  soap  or  an  alkali. 

The  essential  action  of  these  drugs  upon  the  bowel  is  that  of  a 
stimulant  to  peristalsis  (Ascher  and  Spiro).  When  they  were 
placed  in  isolated  loops  of  intestine,  Brieger  with  dogs,  and 
Flemming  with  rabbits,  found  no  increase  of  intestinal  secretion 
and  no  evidence  of  inflammation.  Indeed,  when  placed  in  such 
loops  they  tend  to  be  absorbed.  Magnus  found  that  senna  acted 
in  the  large  intestine  only,  and  it  is  highly  probable  that  this  is 
the  case  with  the  other  drugs  of  the  class.  Their  cathartic  effect 
usually  appears  in  from  seven  to  twelve  hours,  the  stools  after 
an  ordinary  dose  being  soft,  but  not  usually  liquid.  When  the 
muscular  action  is  excessive,  cramp  or  griping  results;  and  a  little 
griping  just  preceding  the  time  of  the  stool  is  very  common. 
It  is  claimed  that  resinous  bodies  are  the  cause  of  this,  and  not 
the  cathartic  principles.  Though  these  drugs  are  mildly  irritant, 
even  large  doses  do  not  produce  inflammation  of  the  intestine ;  but 
if  they  are  not  carried  out,  the  active  principles,  because  of  their 
absorbability,  pass  from  the  intestine  into  the  blood  and  produce 
systemic  symptoms.  One  of  the  author's  patients  took  1  ounce 
(30  c.c.)  of  the  fluidextract  of  cascara,  and,  besides  the  diarrhea, 
had  excitement,  hallucinations,  weakness  of  the  legs,  and  a  mild 


THE   ANTHRACENE    DERIVATIVES 


I23 


degree  of  collapse.  She  had  completely  recovered  twenty  hours 
later. 

Therapeutics. — Beyond  all  other  drugs,  the  anthracene  de- 
rivatives are  preferred  in  habitual  constipation,  especially  that  of 
the  atonic  type.  They  are  not  so  good  in  spastic  constipation. 
By  long  experience  it  has  been  found  that  they  do  not  to  any  great 
extent  lose  their  efficiency  by  repeated  use,  and  in  many  instances 
are  taken  daily,  year  in  and  year  out,  without  even  the  necessity 
of  increasing  the  dose.  It  has  been  noted  further  that  often  a 
small  dose  taken  three  times  a  day  will  be  just  as  efficient  as  a 
much  larger  total  quantity  taken  in  one  dose  at  bedtime.  Aloes 
in  the  larger  doses  is  especially  prone  to  produce  congestion  of  the 
rectum  and  pelvic  organs,  and  consequently  must  be  used  with 
caution  during  menstruation  and  pregnancy  or  if  there  are 
hemorrhoids.  Rhubarb,  frangula,  cascara,  and  senna  contain 
tannic  acid.  When  they  are  used  as  brisk  cathartics,  the  purga- 
tion is  frequently  succeeded  by  constipation.  This  effect  has 
been  attributed  to  the  large  proportion  of  tannic  acid,  but  is 
probably  due  rather  to  the  thorough  emptying  of  the  bowel, 
which  in  chronic  constipation  takes  a  long  time  to  refill.  The 
urine  from  rhubarb  is  yellow  from  chrysophanic  acid,  which  turns 
purple  on  the  addition  of  alkalies.  The  stools  are  also  yellow. 
Frangula,  or  buckthorn,  in  addition  to  its  cathartic  principles, 
contains  amygdalin,  similar  to  that  of  bitter  almonds,  and  some 
free  hydrocyanic  acid  (Blyth).  It  is  stronger  and  harsher  than 
cascara,  and  is  employed  chiefly  by  the  veterinarians.  Senna, 
in  the  form  of  a  decoction  (senna  tea),  is  a  favorite  household 
remedy.     It  is  prone  to  gripe. 

Preparations  and  Doses. — i.  Aloes  (Aloe). — Dose,  4  grains 
(0.25  gm.). 

Extract  of  aloes,  an  aqueous  extract,  dose,  2  grains  (0.13  gm.). 

Purified  aloes  (aloes  purificata) — aloes  softened  by  heat,  mixed 
with  alcohol,  and  strained  while  hot  to  remove  sticks,  sand,  etc. 
Dose,  4  grains  (0.25  gm.).  All  the  other  official  preparations 
are  made  from  purified  aloes.     They  are: 

Liquids. — Tincture  of  aloes,  10  per  cent.  Tincture  of  aloes 
and  myrrh,  of  each,  10  per  cent. 

Pills — Aloes,  each,  2  grains  (0.13  gm.)  with  soap  ;  aloes 
and  iron,  1  grain  (0.07  gm.) ;  aloes  and  mastic  (Lady  Webster's 
dinner  pills),  2  grains  (0.13  gm.);  aloes  and  myrrh,  2  grains  (0.13 
gm.);  and  compound  rhubarb  pills,  ilA  grains  (0.1  gm.),  in  each 
pill. 

Aloin  (aloinum),  the  active  principle,  is  a  mixture  of  anthra- 
cene derivatives.  It  varies  somewhat  according  to  the  kind  of 
aloes  from  which  it  is  extracted,  and  is  named  to  correspond. 


124  PHARMACOLOGY   AND    THERAPEUTICS 

For  example,  barbaloin  is  from  Barbados  aloes,  socaloin  from 
Socotrine  aloes,  and  nataloin  from  Natal  aloes.  The  U.  S.  T. 
dose  is  i  grain  (0.06  gm.),  but  the  usual  dose  for  habitual  consti- 
pation is  about  -g-  grain  (0.013  gm.).  It  is  frequently  employed 
alone  in  pill  or  tablet  triturate,  and  it  enters  into  the  compound 
laxative  pills,  better  known  as  Pil.  A.B.S.  and  I.  Their  formula 
is  aloin,  \  grain  (0.013  gm.);  extract  of  belladonna,  ^  grain 
(0.008  gm.);  strychnine,  the  pure  alkaloid,  ytw  grain  (0.0005 
gm.) ;  and  ipecac,  |-  grain  (0.004  gm-)  in  each  pill. 

2.  Frangula  (Rhamnus  frangula),  dose,  15  grains  (1  gm.), 
has  an  official  fluidextract. 

3.  Cascara  sagrada  (Rhamnus  Purshiana),  dose,  15  grains 
(1  gm.);  extract,  4  grains  (0.25  gm.);  fluidextract,  15  minims 
(1  c.c);  aromatic  fluidextract  (cascara,  glycerin,  25  per  cent., 
licorice,  magnesia,  and  compound  spirit  of  orange),  15  minims 
(1  c.c).  Magnesia  is  said  to  lessen  the  bitter  taste.  The  fluid- 
extracts  may  be  given  in  doses  of  10  minims  (0.7  c.c.)  three  times 
a  day,  or  1  dram  (4  c.c.)  at  bedtime,  with  about  equal  effect. 
The  aromatic  fluidextract  was  designed  to  lessen  the  bitter  taste 
and  to  prevent  griping. 

4.  Rhubarb  (rheum),  dose,  15  grains  (1  gm.);  extract,  4  grains 
(0.25  gm.);  fluidextract,  15  minims  (1  c.c);  aromatic  tincture 
(rhubarb,  20  per  cent.,  with  cinnamon,  cloves,  and  nutmeg), 
]/2  dram  (2  c.c);  syrup,  10  per  cent.,  1  dram  (4  c.c);  aromatic 
syrup,  10  per  cent,  of  the  aromatic  tincture,  2  drams  (8  c.c). 
The  syrups  are  favorites  for  children.  Rhubarb  and  soda  mixture 
(rhubarb,  1.5;  ipecac,  0.3;  sodium  bicarbonate,  3.5;  spirit  of 
peppermint,  3.5;  glycerin,  35  per  cent.,  and  water),  2  drams 
(8  c.c),  and  compound  rhubarb  powder  (rhubarb,  25;  magnesium 
oxide,  65;  and  ginger,  10)  are  antacid  laxatives.  Compound 
rhubarb  pills  contain  rhubarb,  2  grains  (0.13  gm.),  and  purified 
aloes,  1^2  grains  (0.1  gm.),  with  myrrh  and  oil  of  peppermint, 
dose,  2  pills. 

5.  Senna  (senna),  dose,  yi  dram  (2  gm.);  fluidextract,  ]/2 
dram  (2  c.c);  syrup,  20  per  cent.,  2  drams  (8  c.c);  compound 
syrup  of  sarsaparilla  (senna,  1.5  per  'cent.,  with  licorice,  sarsa- 
parilla,  and  aromatics),  4  drams  (15  c.c);  compound  infusion 
(senna,  6;  manna  and  magnesium  sulphate,  each,  12 ;  and  fennel, 
2  per  cent.),  2  ounces  (60  c.c);  confection  (senna,  10  per  cent.; 
tamarind,  cassia  fistula,  prune,  fig,  sugar,  oil  of  coriander),  1 
dram  (4  gm.);  compound  licorice  powder  (senna,  18;  licorice  root, 
23.6;  washed  sulphur,  8;  oil  of  fennel,  0.4;  and  sugar,  50),  1 
dram  (4  gm.).     This  last  is  taken  stirred  up  with  water. 

The  Laxative  Phthaleins. — Phenolphthalein,  not  official,  dose, 


THE   DRASTICS  I  25 

2  grains  (0.13  gm.),  has  a  mild,  non-griping,  laxative  effect.  It 
probably  acts  mostly  by  stimulating  peristalsis,  but  also  to  some 
extent  by  preventing  absorption.  The  effect  is  a  soft,  rather 
large  stool.  In  a  Moreau's  loop  Wood  found  it  unabsorbed  after 
two  hours  and  the  contents  of  the  loop  increased  in  bulk,  but 
he  does  not  say  whether  this  was  due  to  osmosis  or  secretion. 
No  phenol  is  liberated,  and  doses  in  dogs  equivalent  to  from  60 
to  100  grains  in  humans  have  proved  non-toxic  (Wood).  Enor- 
mous doses  intravenously  have  proved  non-toxic  (Abel  and 
Rowntree).  According  to  Rowntree,  it  is  eliminated  by  the 
feces,  and  none  usually  appears  in  the  urine,  except  after  a  hypo- 
dermatic dose.  But  the  author  has  repeatedly  found  it  in  the  urine 
— an  alkaline  urine  after  small  doses  by  mouth  being  of  a  pink 
color  from  its  presence  (this  might  come  from  mere  traces).  A 
very  mild  and  useful  combination  is  phenolphthale'in-agar,  of 
which  a  level  teaspoonful  weighs  about  15  grains  (1  gm.)  and  con- 
tains Yz  grain  (0.03  gm.)  of  phenolphthale'in.  It  sometimes 
produces  nausea  after  a  few  days'  use. 

Phenol-tetrachlorphthalein  is  considered  by  Abel  and  Rown- 
tree the  best  of  the  phthale'ins  for  subcutaneous  use.  They  rec- 
ommend a  solution  made  at  2100  C.  of  6  grains  (0.4  gm.)  in  20 
c.c.  of  neutral  olive  oil,  cooled  to  about  400  C.  and  immediately 
injected  in  the  gluteal  region.  The  drug  does  not  act  usually 
for  eighteen  to  twenty-four  hours,  presumably  because  of  very 
slow  absorption.  After  that  it  gives  a  regular  morning  stool 
which  may  continue  for  days  after  the  administration  is  stopped 
(Rowntree).  It  continues  to  be  excreted  in  the  bile  of  a  dog  with 
a  biliary  fistula  for  forty-eight  to  seventy-two  hours,  and  in  the 
feces  of  a  normal  dog  as  much  as  six  days,  but  not  even  a  trace 
ever  appears  in  the  urine.  The  difficulties  of  its  administration 
forbid  its  coming  into  general  use.  Diacetyl-phenolphthalein 
and  other  phthale'ins  have  also  been  tried  by  mouth,  and  sub- 
cutaneously  in  oily  suspension,  but  clinical  reports  are  not  yet 
decisive  as  to  their  action.  A  proprietary  mixture  of  valeryl 
and  acetyl  phenolphthale'ins  is  called  aperitol,  dose,  10  grains 
(0.7  gm.). 

(e)  THE  DRASTICS 

These  are  so  named  because  their  action  is  harsh.  In  over- 
doses they  tend  to  produce  violent  inflammations.  Their  active 
principles  are  chiefly  resinous  glucosides,  such  as  colocynthin  in 
colocynth  and  jalapin  in  jalap,  or  acids;  such  as  cambogic  in 
gamboge  and  crotonic  in  croton  oil. 

Action  and  Uses. — The  drastics  are  strong  local  irritants, 
acting  to  increase  both  peristalsis  and  secretion.     If  one  of  them 


126  PHARMACOLOGY  AND   THERAPEUTICS 

is  placed  in  a  loop  of  intestine  tied  off  without  injury  to  the 
vessels  (a  Moreau's  loop),  the  wall  of  the  loop  soon  becomes  con- 
gested and  shows  signs  of  inflammation,  and  the  contents  of  the 
loop  contain  inflammatory  products.  Their  cathartic  action  is 
often  accompanied  by  violent  cramps  and  abdominal  soreness, 
and  in  this  event  may  result  in  stools  containing  blood  or  serum- 
albumin.  After  the  larger  doses  in  man,  if  catharsis  does  not 
result  in  a  reasonable  time,  the  drugs  accumulate  in  the  cecum  and 
colon,  and  may  cause  serious  inflammation.  In  such  case,  too, 
they  may  be  slowly  absorbed  and  passed  out  by  the  kidneys, 
and  these  they  irritate  severely,  even  to  the  production  of  an 
acute  nephritis. 

The  writer  saw  a  case  of  hysteria  which  had  been  treated  for 
obstinate  constipation  by  the  administration,  in  a  period  of 
twenty-four  hours,  of  a  seidlitz  powder,  three  compound  cathartic 
pills,  2  drams  (8  gm.)  of  compound  jalap  powder,  and  3  minims 
(0.2  c.c.)  of  croton  oil.  These  resulted  in  no  movement  of  the 
bowels  until  shortly  after  the  last  dose.  Then  there  was  a  violent 
diarrhea,  with  blood  in  the  stools,  severe  abdominal  cramps, 
bloody  urine,  and  later  suppression  of  urine.  The  patient  went 
into  collapse  and  died  in  twenty-four  hours.  At  postmortem 
examination  there  was  an  intense  inflammation  of  the  last  few 
inches  of  the  ileum  and  the  whole  cecum,  in  which  region  some 
brown  drug  was  visible  clinging  to  the  wall  of  the  bowel.  There 
was  also  an  acute  hemorrhagic  nephritis.  The  drastics  had 
caused  these  lesions. 

On  Dr.  Theodore  Janeway's  service  at  St.  Luke's  Hospital 
a  girl  of  nineteen  was  admitted  with  similar  but  less  severe 
poisoning  from  "bitter  apple"  (colocynth),  given  to  her  by  a 
druggist.  She  had  vomited  six  hours  after  the  dose,  and  re- 
peatedly for  twenty-four  hours,  with  almost  constant  diarrhea 
and  a  dull  ache  across  the  lower  abdomen.  She  was  admitted 
the  following  day  to  the  hospital,  the  temperature  being  99. 8°  F., 
the  pulse  116,  and  the  leukocytes  27,200,  with  82.5  per  cent,  of 
polymorphonuclears.  She  still  had  the  gastro-enteritis,  and 
vomited  twice  after  admission ;  but  the  kidneys  were  apparently 
unaffected,  probably  owing  to  the  free  diarrhea.  The  patient 
made  an  uneventful  recovery  in  four  days. 

In  poisoning,  the  immediate  indications  for  treatment  are: 
(1)  To  remove  the  poison  by  a  saline  cathartic  or  castor  oil  or 
by  colon  irrigation,  and  (2)  to  check  collapse.  After  the  immedi- 
ate clearing  out,  bland  oils  or  bismuth  salts  in  large  amounts 
may  be  given.  The  subsequent  treatment  is  that  for  acute 
colitis,  as  by  bland  diet  and  bismuth  salts  by  mouth,  warm  oil 


•K. 


THE    DRASTICS  1 27 

by  rectum,  etc.  If  the  kidneys  are  affected,  the  treatment  for 
acute  nephritis  is  called  for. 

Therapeutics. — It  will  be  seen  that  these  drugs  are  not  suit- 
able for  daily  administration.  Their  repeated  use  tends  to  pro- 
duce ultimate  constipation  by  accustoming  the  bowel  to  excessive 
stimulation,  and  so  lessening  its  sensitiveness.  Their  employ- 
ment should  be  occasional  only,  and  then  only  when  a  thorough 
cleaning  out  of  stagnating  intestinal  contents  is  desired.  On 
account  of  their  tendency  to  gripe,  which  is  very  great,  they 
should  also  be  given  with  correctives,  such  as  the  extract  of 
belladonna  and  aromatics.  In  a  number  of  instances  a  serious 
drop  in  blood-pressure  has  been  noted  during  their  action. 

Of  the  individuals,  podophyllum,  euonymus,  and  leptandra  are 
rather  mild  and  slow  in  action.  Elaterin  tends  to  produce  such 
copious  watery  stools  that  it  is  a  favorite  in  dropsy.  Croton 
oil  is  a  fixed  oil  which  contains  as  its  active  principle  crotonic 
acid,  a  substance  so  irritant  that  a  drop  of  the  oil  in  contact 
with  the  skin  for  an  hour  or  two  results  in  the  formation  of  a 
pustule.  A  drop  applied  to  the  tongue  will  sometimes  move  the 
bowels,  even  if  the  patient  is  comatose.  If  the  oil  is  previously 
freed  from  crotonic  acid,  it  has  an  action  similar  to  that  of  castor 
oil,  and  a  large  dose  is  necessary  to  move  the  bowels.  But  in 
the  oil  as  we  employ  it  this  action  is  entirely  overshadowed  by 
the  action  of  the  crotonic  acid;  hence  the  drug  as  used  is  not  of 
the  castor-oil  type,  but  is  a  powerful  drastic.  Croton  oil  is 
employed  only  occasionally,  and  then  only  in  rebellious  or  coma- 
tose cases.  It  was  formerly  employed  as  a  pustulant  in  pleurisy, 
pneumonia,  etc.,  but  this  use  of  it  has  been  abandoned.  Its 
dose  is  2  minims  (0.13  c.c),  and  each  drop  measures  practically 
1  minim  (0.06  c.c). 

Cautions. — As  the  drastics  are  emmenagogue  and  aborti- 
facient,  they  must  be  used  with  great  caution,  if  at  all,  during 
menstruation  and  pregnancy.  As  they  are  irritant  and  decidedly 
depressing,  they  should  not  be  employed  in  nephritis,  bowel 
inflammations,  hemorrhoids,  and  low  conditions  of  vitality, 
or  in  old  age. 

Preparations  and  Doses. — Elaterin,  yg-  grain  (0.006  gm.); 
resin  of  podophyllum,  %  grain  (0.015  gm-)l  colocynth  (bitter 
apple),  1  grain  (0.06  gm.);  croton  oil  (oleum  tiglii),  2  minims 
(0.13  c.c);  gamboge,  extract  of  euonymus,  resin  of  jalap,  and 
resin  of  scammony,  each,  2  grains  (0.13  gm.);  scammony,  4 
grains  (0.25  gm.);  euonymus,  podophyllum,  and  compound  ex- 
tract of  colocynth,  each,  7^2  grains  (0.5  gm.);  leptandra  and  jalap, 
each,  15  grains  (1  gm.). 

There  are  official,  one  drastic  powder  and  two  drastic  pills, 


128  PHARMACOLOGY  AND    THERAPEUTICS 

viz.,  compound  jalap  powder  (pulvis  jalapae  compositus),  composed 
of  jalap,  35  parts,  and  potassium  bitartrate,  65  parts;  dose,  30 
grains  (2  gm.).     The  pills  are: 

Compound  cathartic  pills  (pilulae  catharticae  compositae),  con- 
taining calomel  and  compound  extract  of  colocynth,  each,  1  grain 
(0.06  gm.),  resin  of  jalap,  f^  grain  (0.02  gm.),  and  gamboge,  % 
grain  (0.015  gm.)  in  each  pill.  They  have  not  sufficient  correc- 
tive and  may  gripe  severely.     Dose,  3  pills. 

Vegetable  cathartic  pills  (pilulae  catharticae  vegetabiles) ,  con- 
taining compound  extract  of  colocynth,  1  grain  (0.06  gm.); 
resin  of  jalap,  ~x\  grain  (0.02  gm.);  resin  of  podophyllum,  % 
grain  (0.015  gm.);  extract  of  leptandra,  ]4,  grain  (0.015  gm-)'> 
extract  of  hyoscyamus,  ^2  grain  (0.03  gm.),  and  oil  of  peppermint, 
\  minim  (0.008  c.c),  in  each  pill.  They  contain  sufficient 
corrective,  and  the  griping  is  slight  or  none.     Dose,  3  pills. 

The  compound  extract  of  colocynth  is  composed  of  purified 
aloes,  50  per  cent.;  extract  of  colocynth,  16  per  cent.;  and  resin 
of  scammony,  14  per  cent.,  with  cardamom  and  Castile  soap. 

Subcutaneous  Purgatives. — A  number  of  active  principles 
will  cause  purgation  when  administered  hypodermatically,  but 
most  of  them,  such  as  aloin,  cascarin,  cathartinic  acid,  colocynthin, 
and  podophyllotoxin  (the  active  principle  of  podophyllin)  are  too 
irritant  locally  for  such  use  in  medicine.  But  physostigmine  salts, 
-3V  grain  (0.001  gm.),  or  hormonal,  30  c.c,  or  phenoltetrachlor- 
phthaleiin,  5  grains  (0.3  gm.),  the  last  named  dissolved  in  oil  by 
heat,  may  be  employed. 

In  almost  all  cases  in  which  a  hypodermatic  cathartic  is  desired 
physostigmine  is  preferred.  It  is  sometimes  very  effective  in 
post-operative  obstinate  constipation  or  tympanites.  (See 
Physostigmine.) 

Saline  Cathartics 

The  saline  cathartics  are  certain  salts  of  sodium,  potassium, 
and  magnesium.  In  the  study  of  salts  it  has  been  found  that 
their  power  of  penetrating  animal  membranes,  or,  in  the  intes- 
tines, their  absorbability,  depends  on  the  nature  of  the  ions  of 
which  they  are  composed.  Of  ready  absorbability,  the  cations 
(positive  ions)  are  ammonium,  potassium,  sodium,  and  lithium; 
and  the  anions  (negative  ions)  are  chlorides,  bromides,  iodides, 
nitrates,  and  acetates.  Among  those  that  are  absorbed  with 
difficulty  are  the  cations,  calcium,  magnesium,  cerium,  aluminium, 
and  the  heavy  metals;  and  the  anions,  phosphates,  sulphates, 
tartrates,  citrates,  malates,  and  lactates.  Of  all  these,  mag- 
nesium among  the  basic  ions,  and  citrates,  phosphates,  sulphates, 
and  tartrates  among  the  acid  ions,  tend  to  give  cathartic  proper- 
ties to  their  compounds.     To  possess  this  property,  the  salt  must 


SALINE   CATHARTICS 


129 


be  in  solution  in  the  intestines.  (Leathes  and  Starling  have 
found  that  the  pleural  endothelium  absorbed  solutions  of  mag- 
nesium sulphate  and  sodium  sulphate,  just  as  quickly  as  solu- 
tions of  sodium  chloride,  but  this  is  not  true  of  the  intestinal  wall.) 
Preparations  and  Doses. — 1.  Of  magnesium — the  oxide,  a 
very  light  powder,  dose,  30  grains  (2  gm.) ;  the  hydroxide,  in  the 
form  of  milk  of  magnesia,  dose,  2  drams  (8  c.c.) ;  and  the  car- 
bonate, dose,  45  grains  (3  gm.),  are  very  mildly  laxative.  The 
laxative  powers  of  these  insoluble  magnesium  salts  are  presumably 
due  to  the  formation  of  the  soluble  chloride  in  the  stomach,  or  the 
soluble  bicarbonate  in  the  intestine.  In  some  cases  they  fail  to  dis- 
solve, and  in  such  have  been  known  to  form  intestinal  concretions 
of  dimensions  large  enough  to  cause  obstruction  of  the  bowels. 
The  hydroxide  is  the  favorite  for  children.  The  citrate  (liquor 
magnesii  citratis),  dose,  half  to  one  bottle  of  12  ounces  (360  c.c); 
the  sulphate  (Epsom  salt),  dose,  )4  ounce  (15  gm.),  very  soluble 
in  water;  and  the  effervescing  sulphate,  dose,  1  ounce  (30  gm.), 
are  more  vigorous. 

2.  Of  potassium — the  citrate,  30  grains  (2  gm.);  the  effer- 
vescing citrate,  60  grains  (4  gm.);  the  bitartrate  (cream  of  tartar), 
30  grains  (2  gm.);   and  the  sulphate,  30  grains  (2  gm.). 

3.  Of  sodium — the  phosphate,  30  grains  (2  gm.);  the  effer- 
vescing phosphate,  2  drams  (8  gm.) ;  the  sulphate  (Glauber's  salt) ; 
2  drams  (8  gm.);  and  the  citrate,  30  grains  (2  gm.). 

The  potassium  and  sodium  tartrate,  KNaC4H406,  is  Rochelle 
salt,  dose,  2  drams  (8  gm.).  The  seidlitz  powder  is  made  by 
inclosing  tartaric  acid  in  a  white  paper,  and  a  mixture  of  Rochelle 
salt  and  sodium  bicarbonate  in  a  blue  paper.  The  contents  of 
the  papers  should  be  dissolved  separately  in  water,  the  two  solu- 
tions mixed,  and  the  liquid  drunk  as  soon  as  the  violent  effer- 
vescence has  ceased.  It  contains  Rochelle  salt,  2  drams  (8  gm.), 
and  some  acid  sodium  tartrate  formed  during  effervescence. 
Potassium  bitartrate,  KHC4H406,  is  soluble  with  difficulty  in 
water,  but  it  forms  Rochelle  salt  in  the  duodenum. 

The  effervescent  preparations  are  usually  preferred,  as  the 
CO2  present  renders  them  more  palatable  and  less  nauseating. 
They  are  the  solution  of  citrate  of  magnesia,  the  effervescing 
citrate  of  potassium,  phosphate  of  sodium,  and  sulphate  of  mag- 
nesium, and  the  seidlitz  powder.  The  laxative  mineral  waters 
usually  contain  sodium  sulphate  or  magnesium  salts. 

Pharmacologic  Action. — Skin  and  Mucous  Membranes.— 
Applied  to  the  skin,  solutions  of  these  salts  are  practically  inert, 
as  they  penetrate  the  horny  epithelium  wit^i  difficulty.  Applied 
to  mucous  membranes,  the  concentrated  solutions  are  rather 
irritant  because  of  the  abstraction  of  water. 
9 


130  PHARMACOLOGY   AND    THERAPEUTICS 

Stomach. — Solutions  of  salts  in  fairly  concentrated  form,  as 
they  are  administered  for  cathartic  effects,  have  an  unpleasant 
salt  taste  and  are  irritant  to  the  stomach,  hence  they  tend  to  be 
nauseating.  If  they  lie  in  the  stomach,  they  promote  transuda- 
tion and  secretion,  and  therefore  their  own  dilution.  The  view 
of  Otto  (1905)  that  solutions  of  salts  are  retained  in  the  stomach 
until  they  become  isotonic  with  the  body  fluids  has  been  in  the 
main  corroborated,  and  Hertz  (1910)  concludes  that  "even  very 
concentrated  solutions  become  almost  isotonic  before  their  evacu- 
ation from  the  stomach."  Brown  (191 2)  found  that  hypertonic 
solutions  were  markedly  retarded  in  the  stomach,  and  that  iso- 
tonic and  hypotonic  solutions  leave  less  rapidly  than  the  very 
hypotonic  tap-water.  He  agrees  with  Leven  and  Barrett  that 
from  an  otherwise  empty  stomach  200  c.c.  of  water  leave  in  about 
twenty  minutes.  In  his  experiments  he  ascertained  that  the 
strong  laxative  mineral  waters  call  forth  considerable  transuda- 
tion in  the  stomach  and  some  secretion  of  gastric  juice,  and 
strongly  inhibit  the  motor  functions.  They  are  irritant  and  are 
capable  of  inducing  an  acute  gastritis.  In  their  administration, 
they  should  be  properly  diluted  to  bring  them  nearly  to  an  iso- 
tonic condition.  For  example,  Hunyadi  and  Friedrichshall 
should  be  followed  by  an  equal  amount  of  water;  magnesium 
sulphate  should  be  given  in  7.5  per  cent,  solution  (isotonic); 
sodium  sulphate,  in  about  2  per  cent.,  and  Carlsbad  salts  in 
about  3  per  cent.,  solution. 

The  amount  of  fluid  added  by  the  stomach  may  be  quite 
large;  for  instance,  by  a  high  duodenal  fistula  Brown  obtained 
503  c.c.  after  150  c.c.  of  Hunyadi  water,  and  250  c.c.  after  150 
c.c.  of  50  per  cent.  Hunyadi  water  (almost  isotonic). 

Intestines. — Some  years  ago  Hober,  Wallace,  and  Cushny 
administered  solutions  of  various  salts  to  dogs.  On  analysis  of 
the  contents  of  the  intestines  they  found  that  the  salts  which 
were  cathartic  were  regularly  the  ones  not  readily  absorbed, 
and  that  these  acted  as  cathartics  even  when  in  solutions  isotonic 
with  the  blood.  By  means  of  a  cecal  fistula  they  also  measured 
the  fluid  that  reached  the  cecum  after  the  administration  of 
isotonic  solutions.  After  100  c.c.  of  sodium  chloride  solution 
there  was  none  recovered  at  the  cecum  in  one  hour :  it  had  been 
absorbed.  After  100  c.c.  of  sodium  citrate,  75  c.c.  were  recovered, 
and  after  100  c.c.  of  sodium  sulphate,  from  80  to  90  c.c.  were  re- 
covered. They  concluded  that  from  75  to  90  per  cent,  of  ca- 
thartic salts,  with  the  fluid  in  which  they  were  dissolved,  was 
unabsorbed;  and  that  the  catharsis  was  due  to  the  large  bulk  of 
fluid  and  not  to  any  active  stimulation  of  the  intestinal  wall. 
Boas  found  that,   as  the  solution  was  more  concentrated,  it 


SALINE   CATHARTICS  131 

proved  less  cathartic  and  more  prone  to  be  absorbed  and  to  pro- 
duce systemic  effects.  He  reports  10  cases  of  magnesium 
poisoning  from  concentrated  doses  of  Epsom  salts.  Meltzer, 
Lucus,  and  Auer  have  pointed  out  that  when  magnesium  sul- 
phate is  administered  intravenously  it  reduces  the  irritability 
of  the  intestines  and  checks  the  peristalsis  aroused  by  physos- 
tigmine  or  barium  chloride.  Magnus  has  shown  that  magnesium 
sulphate  has  no  power  of  itself  to  stimulate  peristalsis,  and  Cohn- 
heim  placed  it  in  the  duodenum,  with  no  effect  on  the  motility 
of  the  bowel.  These  findings  corroborate  the  belief  that  the 
bulk  of  unabsorbed  fluid  is  the  laxative  agent. 

On  the  other  hand,  a  theory  propounded  by  Aubert  (1852), 
that  the  salts  had  to  be  absorbed  in  order  to  act  on  the  intestine, 
received  some  corroboration  by  the  work  of  J.  B.  MacCallum 
(1904).  He  found  that  laxative  salines  (sodium  citrate  and 
sulphate)  administered  intravenously  were  cathartic.  This 
has  not  proved,  however,  to  be  regularly  the  case,  and  investi- 
gators have  considered  the  theory  untenable.  However,  Hertz 
(1910),  after  numerous  studies  with  the  x-rays,  has  revived  the 
theory.  He  discovered  that  in  two  patients  with  fistula  at 
the  end  of  the  ileum  the  soluble  purgative  salt  traveled  no  faster 
than  the  heavy  bismuth  salt  given  with  it,  so  he  assumed. that 
it  was  fair  to  judge  by  x-ray  pictures  and  by  auscultation  of  the 
cecal  sounds.  The  x-rays  showed  that  though  a  watery  stool 
was  passed  one  and  a  half  hours  after  the  saline  was  taken,  the 
bismuth  given  with  the  saline  did  not  reach  the  cecum  for  four 
hours.  He  showed  further  that  in  the  watery  stools  from  sodium 
sulphate  there  was  no  increase  in  the  sulphates;  that  half  the 
salt  was  excreted  in  the  urine  in  eight  hours ;  and  that  the  greater 
part  of  the  salt  of  the  feces  appeared  the  next  day  after  the 
liquid  stools  had  ceased.  He  concluded  that  the  salt  must  have 
been  absorbed,  that  it  acted  through  the  blood  as  a  stimulant 
both  to  secretion  and  to  peristalsis  of  the  colon,  and  that  it  acted 
independently  of  its  own  appearance  in  the  colon. 

However,  a  saline  administered  by  mouth  but  prevented  from 
reaching  the  colon  is  not  cathartic,  and  hypodermatic  or  intra- 
venous doses  are  not  cathartic;  indeed,  Auer  says  that  an  intra- 
venous or  hypodermatic  dose  definitely  checks  peristalsis.  Mac- 
Callum attributed  the  failure  of  the  intravenous  dose  to  too  rapid 
excretion  by  the  kidneys,  and  believed  that  only  through  the 
intestines  could  a  sufficient  concentration  of  the  salt  be  absorbed 
for  cathartic  effect. 

MacCallum  suggested  that  salts  are  purgative  by  precipitat- 
ing the  calcium  salts  in  the  tissues  and  so  neutralizing  their  de- 
pressing action.     And,  as  a  matter  of  fact,  the  cathartic  com- 


13 2  PHARMACOLOGY  AND    THERAPEUTICS 

pounds  are,  for  the  most  part,  the  ones  that  precipitate  calcium, 
and  calcium  tends  to  inhibit  their  cathartic  action. 

It  is  usual  that  in  one  or  two  hours  the  dose  results  in  one  or 
more  watery  stools,  which  consist  of — (i)  the  salt  and  the  water 
in  which  it  is  dissolved;  (2)  some  of  the  gastro-intestinal  con- 
tents of  which  absorption  is  prevented  by  the  salt;  (3)  some  of 
the  feces  already  formed  in  the  colon;  and  (4)  liquid  added  by 
transudation  and  secretion.  Bayliss  and  Starling,  Magnus, 
Cannon,  and  others  have  shown  that  the  passage  of  liquids  along 
the  intestine  is  different  from  that  of  solid  or  pasty  matter. 
Solids  stimulate  peiistalsis,  whereas  liquids  simply  generate 
rhythmic  intestinal  segmentations  (Cohnheim).  The  result  of 
this  is  that,  while  the  liquid  passes  along,  more  or  less  of  the  solid 
contents  of  the  intestine  are  likely  to  be  left  behind.  Hence  a 
saline  cathartic  may  not  be  so  thoroughly  cleansing  as  the  ordi- 
nary more  slowly  acting  stimulants  of  peristalsis. 

In  connection  with  saline  cathartics,  Moreau's  loop  has  be- 
come a  classic  experiment.  It  is  a  loop  of  intestine  tied  off  with- 
out injury  to  the  vessels  and  nerves  of  the  mesentery.  Into  such 
loops  different  salt  solutions  are  injected,  and  they  show  that — 
(1)  An  isotonic  solution  remains  almost  unchanged  at  the  end  of 
three  hours;  (2)  a  hypotonic  solution  loses  in  volume,  that  is, 
is  absorbed,  and  (3)  a  hypertonic  liquid  gains  in  volume.  It  is 
of  interest  that  in  the  latter  case  there  is  no  protein  or  other 
evidence  of  inflammation.  The  gain  in  volume  is  due  either  to 
secretion  or  to  osmosis.  However,  as  the  loops  prevent  peristalsis 
and  segmentation,  the  results  of  such  experiments  are  not  at  all 
conclusive  as  to  the  action  of  saline  cathartics. 

Of  saline  cathartics  as  a  class  it  may  be  said  that — 

1.  They  irritate  the  stomach  and  are  prone  to  produce 
nausea,  an  effect  which  may  be  largely  overcome  by  administer- 
ing them  as  effervescent  drinks. 

2.  Their  stools  contain  much  liquid  but  no  inflammatory 
products. 

3.  They  are  often  not  thoroughly  cleansing. 

4.  They  act  most  rapidly  and  best  if  taken  fasting,  as  before 
breakfast,  and  with  a  large  volume  of  water.  Their  action  comes 
on  in  an  hour  or  two. 

5.  Their  catharsis  is  the  effect  of  the  increased  bulk  and 
fluidity  of  the  colon  contents,  and  this  is  chiefly  due  to  the  pre- 
vention of  absorption. 

6.  They  do  not  induce  irritant  griping;  but  accompanying 
their  rapid  passage  through  the  intestines  there  may  be  some 
griping,  much  gurgling  of  the  intestines,  and  more  or  less  faint- 
ness  and  nausea. 


SALINE    CATHARTICS  1 33 

7.  If  they  are  not  evacuated,  they  produce  no  inflammation 
and  are  absorbed. 

8.  When  absorbed,  they  pass  out  by  the  kidneys  and  act  as 
diuretics. 

9.  In  moderately  hypertonic  solutions  they  tend  to  remove 
fluid  from  the  body.  This  may  not,  however,  be  the  case  if  the 
dose  is  repeated  daily,  and  especially  if  the  patient  is  on  a  "dry" 
diet,  as  in  dropsy.  In  such  cases  the  salt  may  be  absorbed  and 
only  add  to  the  work  of  the  kidneys. 

10.  Violent  purging  results  in  nausea,  lowered  blood-pressure, 
and  prostration. 

1 1 .  Small  doses  taken  at  night  tend  to  promote  and  soften 
the  morning  stool. 

Therapeutics  of  Salines. — They  may  be  employed : 

1.  In  acute  constipation — for  a  rapidly  acting  non-irritant 
cathartic.  2.  In  habitual  constipation.  3.  In  intestinal  putre- 
faction. 4.  In  dropsy.  5.  To  lessen  obesity.  6.  To  lessen 
the  secretion  of  milk  in  nursing  mothers. 

The  last  three  effects  are  dependent  upon  the  power  of  salines 
to  decrease  the  fluid  in  the  body.  For  this  purpose  they  are  ad- 
ministered daily,  a  diet  low  in  liquids  being  prescribed.  But 
they  usually  very  soon  cease  to  carry  out  excess  of  liquid, 
and  when  profuse  watery  catharsis  does  not  result,  should  be 
stopped.  They  probably  have  no  influence  on  obesity;  at  any 
rate,  of  themselves  alone  they  are  unable  to  cause  the  body  to 
lose  fat. 

Moderate  doses  make  the  stools  soft  and  non-irritant,  so  have 
been  advised  in  hemorrhoids,  fissure  of  the  anus,  etc.;  large 
doses  cause  such  sudden  expulsion  as  to  be  harmful  in  these  con- 
ditions. 

Objections  to  the  habitual  use  of  salines  in  chronic  constipa- 
tion are — (1)  That  they  accustom  the  intestines  to  a  greater  bulk 
of  contents  than  usual,  so  that  the  intestines  lose  their  sensi- 
tiveness to  the  usual  bulk  of  intestinal  contents;  and  (2)  that 
they  activate  the  intestine  for  one  or  two  hours  only,  and  allow 
it  to  remain  "fallow"  for  the  rest  of  the  twenty-four  hours. 

Poisoning  by  Magnesium  Sulphate. — Magnesium  sulphate 
in  very  concentrated  solution  does  not  induce  peristalsis,  is 
absorbed,  and  is  poisonous.  The  toxic  symptoms  are:  marked 
depression  of  respiration  and  a  curare-like  action  on  the  junctions 
of  motor  nerves  with  striated  muscle  (Meltzer  and  his  associates 
and  Barbier).  The  salt  is  eliminated,  in  the  urine  and  gives  this 
a  very  high  specific  gravity,  even  1070  or  1080,  which  of  itself 
is  suggestive  of  magnesium  sulphate  poisoning.  The  antidotes 
are. calcium  or  physostigmine  (Meltzer  and  Joseph). 


134  PHARMACOLOGY  AND   THERAPEUTICS 

RECTAL  TREATMENT 

Enemata,  or  rectal  injections,  may  be  for  cathartic,  nutritive, 
or  cleansing  purposes,  or  they  may  be  employed  to  supply  liquid 
to  the  body,  to  cause  the  expulsion  of  gas,  or  to  carry  local  reme- 
dies to  the  mucous  membrane  of  rectum  and  colon. 

The  cathartic  enema  may  be  employed  both  as  a  softening 
agent  for  feces  and  as  an  evacuant.  It  has  the  advantage  of 
affecting  directly  the  rectal  reservoir  and  its  contents,  (a) 
The  softening  agents  are  water,  soapsuds,  olive  oil,  glycerin,  and 
oxgall.  Hertz  found  that  hard  fecal  masses  in  contact  with  olive 
oil  were  not  disintegrated  in  twelve  hours,  while  in  contact  with 
water  they  disintegrated  in  four  hours.  Oxgall,  also,  he  found  to 
have  no  greater  softening  power  than  water.  Glycerin  increases 
the  penetration  of  the  water.  In  cases  of  impacted  feces  it  has 
been  the  custom  to  inject  fresh  oxgall  or  a  i  to  3  per  cent,  solu- 
tion of  purified  oxgall  (fel  bovis  purificatum),  or  warm  olive  oil, 
sometimes  with  the  addition  of  castor  oil.  But,  as  just  stated, 
neither  oxgall  nor  olive  oil  is  as  effective  as  water  in  softening 
feces;  and  it  is  a  fact  that  castor  oil  has  little  evacuant  power 
unless  it  is  saponified,  as  in  the  duodenum.  (Inouye  and  Sato 
(191 1)  report  that  inspissated  oxgall,  15  grains  (1  gm.)  by  mouth, 
promotes  the  absorption  of  fat.)  For  softening  impacted  feces, 
therefore,  the  best  enemata  are  plain  water,  normal  saline,  and 
soapsuds,  with  the  addition  of  glycerin,  }4  ounce  (15  c.c.)  to  1 
pint  (500  c.c). 

The  evacuating  enema  acts  either  by  constituents  capable  of 
irritating  the  rectum  or  by  the  mechanical  stimulus  of  its  presence 
in  the  rectum.  It  consists  usually  of  from  one  pint  to  two 
quarts  of  warm  soapsuds,  or  soapsuds  with  the  addition  of  gly- 
cerin, y2  ounce  (15  c.c),  or  oil  of  turpentine,  %  ounce  (15  c.c). 

In  the  cat,  Cannon  has  observed  peristalsis  of  the  small  in- 
testine as  the  result  of  a  rectal  injection  and  antiperistalsis  of  the 
colon.  In  tests  with  bland  nutritive  enemata  of  milk,  eggs, 
starch,  and  bismuth  subnitrate  he  found  that  in  every  instance 
antiperistaltic  waves  carried  the  material  to  the  cecum.  Small 
enemata  never  passed  the  ileocecal  valve,  but  large  enemata  of 
about  the  capacity  of  the  large  intestine  would  often  pass  into 
the  small  intestine. 

In  man,  if  a  quantity  of  liquid  is  introduced  three  or  four 
inches  into  the  rectum,  it  will  not  infrequently  reach  the  cecum  by 
antiperistalsis;  but  this  happens,  as  a  rule,  only  when  the  liquid 
is  bland  and  is  administered  slowly,  so  as  not  to  start  the  defeca- 
tion reflexes.  In  some  cases,  however,  an  enema  does  pass  quickly 
to  the  cecum,  and,  in  rare  instances,  has  been  vomited.  In  these 
cases,  of  course,  the  enema  fails  to  act  as  an  immediate  evacuant. 


RECTAL   TREATMENT  I35 

The  evacuant  enema  is  given  rapidly,  and  by  a  sudden  dis- 
tention of  the  rectum  or  by  direct  irritation  of  the  bowel-wail 
results  reflexly  in  active  forward  peristalsis,  at  least  of  the  de- 
scending colon,  with  expulsive  contraction  of  the  rectum  and 
relaxation  of  the  anal  sphincters. 

In  the  treatment  of  chronic  constipation  enemata  should  not 
be  given  over  too  long  periods,  for  they  accustom  the  bowel  to  the 
stimulus  of  a  bulk  of  material  greater  than  that  of  the  normal  feces. 

Enemata  to  induce  the  expulsion  of  gas  may  be  of  soapsuds 
made  from  yellow  laundry  soap;  of  soapsuds  and  turpentine, 
yi  ounce  (15  c.c);  of  turpentine,  >*>  ounce  (15  c.c),  with  olive 
oil,  6  ounces  (180  c.c.) ;  of  ice  water;  of  infusion  of  chamomile;  or 
of  tincture  of  asafetida,  4  drams  (15  c.c),  or  spirit  of  peppermint, 
1  dram  (4  c.c),  added  to  a  pint  of  hot  water.  They  are  employed 
in  the  tympanites  of  typhoid  fever,  pneumonia,  post-operative 
intestinal  paralysis,  etc. 

Colon  or  rectal  irrigations  of  saline  solution  slowly  admin- 
istered, using  both  inlet  and  outlet  tubes,  are  frequently  employed 
to  clean  out  the  products  of  intestinal  putrefaction,  to  activate 
the  kidneys,  or  to  supply  fluid  after  hemorrhage.  The  inlet  tube 
may  be  inserted  6  or  8  inches,  and  the  outlet  tube  about  half  as  far. 
The,  ''''continuous  drop"  irrigation,  in  which  an  exceedingly  tardy 
flowof  warm  saline  is  kept  up  continuously,  day  and  night,  was  rec- 
ommended by  Murphy  for  post-operative  tympanites  and  shock. 

Nutritive  enemata  are  employed  for  feeding  when  it  is  neces- 
sary to  spare  the  stomach.  They  must  be  small  in  bulk,  i.  e., 
about  6  or  8  ounces  (180-240  c.c),  warmed,  and  slowly  adminis- 
tered so  that  they  will  not  be  expelled.  They  may  be  given  at 
six-  or  eight-hour  intervals,  and  their  administration  should  be 
accompanied  by  a  daily  cleansing  enema  of  normal  saline  or 
weak  soapsuds.  The  ingredients  of  the  enema  should  be  made 
as  absorbable  as  possible.  The  available  foods  are  dextrose, 
sugar,  sugar  of  milk,  fully  peptonized  milk,  whisky,  brandy,  and 
raw  eggs.  The  white  of  egg  peptonized  with  the  milk  may  be 
absorbed,  but  the  ingredients  of  the  yolk  may  not  be.  Dextrose 
solutions  are  absorbable,  but  tend  to  irritate  and  cause  evacua- 
tion. Whether  the  other  sugars  are  inverted  and  absorbed  is  a 
question.  Magnus  says  that  cane-sugar  is  absorbable.  The 
absorption  of  oils  is  promoted  by  emulsification  with  3  to  5  per 
cent,  of  lecithin  (Congdon),  and  this  may  apply  to  egg-yolk. 
It  is  possible  that  the  amino-acids,  such  as  tyrosin,  histidin,  and 
arginin,  may  prove  useful  for  rectal  feeding,  as  they  represent 
the  end-products  of  protein  digestion.  But  they  are  very  sub- 
ject to  putrefactive  decomposition  with  the  formation  of  ali- 
mentary poisons. 


136  PHARMACOLOGY   AND   THERAPEUTICS 

The  rectum  is  a  favorite  channel  for  the  administration  of 
warm  normal  saline  solution  to  supply  liquid  to  the  body  after 
severe  hemorrhage. 

Rectal  suppositories  may  be  of  wheat-gluten,  soap,  glycerin, 
or  plain  or  medicated  cocoa-butter.  The  evacuant  ones  act 
largely  mechanically  as  a  foreign  body,  stimulating  the  rectum 
to  expel  it.  Even  a  stick  of  ice  or  an  undisintegrated  stick  of 
soap  will  often  have  the  same  effect.  Glycerin  suppositories, 
made  of  almost  pure  glycerin,  with  a  little  sodium  stearate  to  give 
a  solid  consistence,  are  much  employed.  The  glycerin  acts  as 
an  irritant  in  the  anal  canal,  but  not  in  the  rectum  (Hertz). 
Suppositories  are  especially  useful  where  the  feces  come  down 
to  the  rectum,  but  are  retarded  in  their  expulsion  by  a  tight  or 
sensitive  sphincter. 

ANTI-DIARRHEICS 

Diarrhea  has  so  many  causes  that  remedies  of  entirely  dif- 
ferent action  may  be  required  in  the  different  types.  In  fer- 
mentative diarrhea  castor  oil  may  be  indicated,  followed  by  a 
bland  protective  like  bismuth  subnitrate.  In  severe  diarrhea 
camphor,  lead  acetate,  or  opium  may  be  the  needed  remedy. 
The  anti-diarrheics  are:  bismuth  salts  (subnitrate,  subcarbonate, 
and  subgallate),  cerium  oxalate,  calcium  carbonate  (chalk), 
camphor,  lead  acetate,  opium,  the  vegetable  astringents,  and 
castor  oil.  They  are  all  studied  in  detail  elsewhere.  The  Sun 
Cholera  Mixture,  N.  F.,  contains  in  each  teaspoonful  6  minims 
(0.4  c.c.)  each  of  the  tinctures  of  capsicum  and  rhubarb,  and  12 
minims  (0.8  c.c.)  each  of  the  spirit  of  camphor,  spirit  of  pepper- 
mint, and  tincture  of  opium.  Dose,  J/2  dram  (2  c.c).  SquibVs 
Diarrhea  Remedy,  N.  F.,  is  made  of  tincture  of  opium  and  spirit 
of  camphor,  each,  7  minims  (0.5  c.c),  tincture  of  capsicum,  4 
minims  (0.25  c.c),  chloroform,  5  minims  (0.3  c.c),  and  alcohol 
enough  to  make  1  dram  (4  c.c).  Dose,  yi  dram  (2  c.c).  Pills 
of  lead  acetate,  2  grains  (0.13  gm.),  and  powdered  opium,  1 
grain  (0.06  gm.),  are  also  employed.  A  favorite  type  of  pre- 
scription in  simple  diarrhea  is:  bismuth  subnitrate,  3  drams 
(12  gm.),  camphorated  tincture  of  opium,  yZ  ounce  (15  c.c), 
and  sufficient  chalk  mixture  to  make  2  ounces  (60  c.c).  Dose, 
a  dessertspoonful  every  two  or  three  hours,  or  after  each  move- 
ment of  the  bowels. 

MINERAL  WATERS 

A  mineral  water  is  a  natural  water  containing  one  or  more 
ingredients  different  from,  or  in  greater  quantity  than,  those  in 


MINERAL   WATERS 


*37 


ordinary  drinking  or  washing  water.  Many  bottled  waters  are 
not  mineral  waters.  As  obtained  from  the  earth,  they  are 
thermal  when  they  are  distinctly  warmer  than  the  average  sur- 
rounding temperature,  otherwise  non-thermal;  some  writers  adopt 
700  F.  as  the  dividing  line  between  these.  Warm  waters  are  those 
from  700  to  98. 6°  F.;  hot  waters  are  those  above  98. 6°  F.  They 
may  be  sparkling  or  effervescent,  i.  e.,  impregnated  with  carbon 
dioxide,  or  still,  i.  e. ,  non-effervescent.  They  may  be  sulphurated, 
containing  hydrogen  sulphide  gas.  Their  mineral  constituents 
are  sodium,  potassium,  lithium,  magnesium,  calcium,  iron, 
aluminium,  and  arsenic,  in  the  form  of  sulphates,  nitrates, 
chlorides,  bromides,  iodides,  borates,  and  silicates.  In  a  number 
of  the  waters  the  percentage  of  the  ingredients  has  been  found 
quite  variable  at  different  seasons  and  in  different  years.  The 
report  of  Haywood  and  Smith  (1905),  of  the  United  States  Bureau 
of  Chemistry,  on  the  "Mineral  Waters  of  the  United  States," 
and  that  of  Francina,  on  "European  Waters,"  furnish  valuable 
data. 

A  medicinal  classification  is  not  readily  made  because  many 
waters  contain  more  than  one  ingredient  of  importance.  All  are 
either — (1)  Alkaline,  i.  e.,  having  an  alkaline  reaction;  this 
comes  from  carbonates  and  bicarbonates,  or  in  a  few  instances 
from  borates  and  silicates.  (2)  Saline,  containing  chlorides, 
nitrates,  or  sulphates  in  excess.  (3)  Alkaline  saline,  combining 
the  properties  of  the  alkaline  and  the  saline,  or  (4)  Acid,  in  which 
there  is  free  sulphuric  or  hydrochloric  acid. 

Any  of  these  may  contain  one  or  other  of  the  special  elements, 
and  are  known  as: 

Sulphur  waters — those  containing  sulphuretted  hydrogen  and 
*other  sulphides.  They  are  usually  from  "red"  or  "white" 
sulphur  springs,  these  names  being  obtained  from  the  precipita- 
tion of  sulphur.  The  red  sulphur  gets  its  color  from  iron.  Ex- 
amples are  the  waters  of  Richfield  Springs  or  Sharon  Springs. 

Chalybeate  or  ferruginous  waters — those  which  contain  iron, 
usually  in  the  form  of  the  sulphate  or  bicarbonate,  as  Spa. 

Arsenical  waters — those  which  contain  arsenic,  as  Levico 
and  Bourboule. 

Alum  waters — those  which  contain  aluminium  salts.  Rock- 
bridge alum  water  contains  337  grains  of  aluminium  sulphate 
per  million  and  is  astringent. 

Bromine  waters,  iodine  waters,  etc. 

Lithia  waters — of  these,  Haywood  and  Crook  say  "lithium 
seldom  or  never  occurs  in  waters  in  large  enough  quantities  to  be 
a  predominating  basic  constituent."  In  their  analyses,  Buffalo 
and  Londonderry  Lithia  Waters  show  only  a  trace,  Otterburn 


138  PHARMACOLOGY   AND   THERAPEUTICS 

Lithia,  0.03  part,  Geneva  Lithia,  0.1  part,  and  White  Rock 
Lithia,  12.6  parts  of  lithium  per  million.  Thus  the  term  "lithia 
water"  is  a  misnomer. 

Examples  of  alkaline  waters  are  Vichy,  Apollinaris,  Seltzer, 
Bear  Lithia,  Great  Bear,  Manitou.  Of  alkaline  saline  are  the 
Saratoga  waters  (Carlsbad,  Congress,  Hathorn,  High  Rock, 
Vichy,  Seltzer)  and  White  Rock  Lithia.  The  Saratoga  waters 
are  much  poorer  in  salts  now  than  formerly.  The  saline  waters 
are  those  containing  abundance  of  salts  and  not  alkaline,  such  as 
Pluto  and  Mount  Clemens. 

Mineral  waters  may  be  used  for  the  bath  or  internally.  At 
the  various  "springs,"  both  the  baths  and  the  drinking  of  the 
waters  are  considered  requisite  parts  of  the  treatment.  It  is 
claimed  that  some  of  the  waters  contain  radium  emanations  and 
are,  therefore,  more  effective  when  taken  fresh. 

From  a  medicinal  point  of  view  the  purgative  waters  are  the 
most  important.  In  nearly  all  cases  they  owe  their  cathartic 
action  to  sodium  sulphate  (Glauber's  salt),  magnesium  sulphate 
(Epsom  salt),  magnesium  chloride,  or  magnesium  bicarbonate. 
The  waters  which  contain  a  large  percentage  of  magnesium  salts 
are  bitter. 

Those  whose  action  is  due  to  sodium  sulphate  alone  are  the 
Carlsbad  waters  and  Marienbad,  which  are  alkaline,  and  Rubinat 
and  Villacabras,  which  are  neutral.  The  published  analyses  of 
the  Carlsbad  waters  differ  considerably  from  one  another. 
Those  owing  their  action  to  both  sodium  sulphate  and  the  mag- 
nesium salts  are:  Pluto,  Friedrichshall,  Carabafia,  and  the 
Hungarian  waters,  Apenta,  Franz  Josef,  and  Hunyadi  Janos. 
"Pluto  concentrated"  does  not  have  its  salts  in  the  same  relative 
proportions  as  Pluto  water.  It  contains  about  65  grains  (4.3' 
gm.)  of  sodium  sulphate  and  30  grains  (2  gm.)  of  magnesium 
sulphate,  in  a  dose  of  2  ounces  (60  c.c). 

Mount  Clemens  water  is  essentially  a  solution  of  magnesium 
chloride. 

REMEDIES  WHOSE  CHIEF  ACTION  IS  UPON  THE  CIR- 
CULATION 

(a)  General  circulatory  stimulants. 

(b)  Measures  to  increase  the  volume  of  the  blood. 

(c)  Cardiac  depressants.    A 

(d)  Arterial  dilators. 

(e)  Measures  to  lessen  the  volume  of  the  blood. 


THE   PHYSIOLOGY   OF   THE   CIRCULATION  139 

THE  PHYSIOLOGY  OF  THE  CIRCULATION 

The  following  is  a  brief  review  from  a  pharmacologic  stand- 
point : 

The  circulatory  organs  are  for  the  purpose  of  carrying  to 
and  from  the  tissues  certain  materials  by  means  of  the  blood; 
and  since  all  exchanges  between  the  blood  and  the  tissues  are 
made  through  the  capillary  walls,  it  may  be  said  that  the  function 
of  the  circulatory  organs  is  to  maintain  an  adequate  capillary 
blood-flow.  Hence  the  circulatory  organs  need  treatment  when 
they  fail  to  maintain  an  adequate  capillary  blood-flow.  This 
capillary  blood-flow  is  dependent  somewhat  upon  the  viscosity 
of  the  blood,  but  mainly  upon  the  relation  between  the  general 
arterial  blood-pressure  (the  driving  force)  and  the  caliber  of  the 
arterioles  which  lead  to  the  capillaries  (the  peripheral  resistance) . 
These  arterioles,  being  actively  contractile,  serve  as  adjustable 
gates  by  means  of  which  the  amount  of  blood  passing  to  any 
given  set  of  capillaries  may  be  regulated.  And  it  is  obvious  that 
if  the  general  arterial  pressure  remains  the  same  an  increase 
in  the  caliber  of  any  given  set  of  arterioles  will  result  in  a  greater 
supply  of  blood  to  the  capillaries  of  that  set;  and  that  if  the 
caliber  of  these  arterioles  remains  the  same,  an  increase  in  the 
general  arterial  pressure  will  have  a  similar  result.  The  adjust- 
ment of  the  caliber  of  individual  sets  of  arterioles  without  pro- 
ducing the  same  changes  in  other  sets  is,  for  the  most  part, 
impossible  therapeutically;  but  the  caliber  of  the  arterioles  as  a 
class  may  be  readily  changed  by  remedial  measures. 

Capillary  flow  may  be  altered  by  changes  in — (i)  The  total 
amount  of  blood  in  the  arterial  system;  (2)  the  heart's  output 
in  a  given  time;  (3)  the  general  peripheral  or  arteriole  resistance, 
and  (4)  the  viscosity  of  the  blood. 

The  amount  of  blood  in  the  arteries  may  be  decreased  by  its 
accumulation  in  the  veins,  by  its  loss  from  the  body  (as  in  hemor- 
rhage or  blood-letting) ,  or  by  the  excessive  removal  of  other  fluid 
from  the  body,  as  in  cholera  or  other  severe  diarrheal  conditions. 
It  may  be  increased,  especially  after  a  preliminary  loss,  as  in 
hemorrhage  or  cholera,  by  increased  receipt  from  the  veins,  by 
transfusion  of  blood,  by  intravenous  administration  of  saline 
solutions,  and  by  rapid  absorption  of  liquid,  e.  g.,  saline  solutions, 
from  the  alimentary  tract.  The  heart's  output  may  be  affected 
by  measures  which  influence  either  the  filling,  the  capacity,  the 
rate,  or  the  strength  of  the  ventricles.  The  peripheral  resistance 
may  be  altered  by  measures  which  change  the  caliber  of  the 
arterioles. 

It  will  be  obvious  that  the  rate  of  capillary  flow  is  not  to  be 
judged  by  the  degree  of  general  arterial  pressure.     For  example, 


140  PHARMACOLOGY  AND  THERAPEUTICS 

suppose  the  heart  increases  its  output,  but  the  arterioles  dilate 
just  enough  to  let  the  additional  blood  through.  Then,  though 
the  general  pressure  remains  unchanged,  yet  more  blood  flows 
through  the  capillaries  and  the  circulation  is  more  active.  As  a 
matter  of  fact,  it  has  been  found  in  man  that  the  mechanisms 
which  control  blood-pressure  are  so  neatly  adjusted  that  it  is 
well-nigh  impossible  to  cause  a  decided  rise  in  arterial  pressure  by 
a  therapeutic  dose  of  any  slowly  acting  drug,  and  yet  some  such 
drugs,  e.  g.,  digitalis,  do  have  great  power  to  improve  the  circula- 
tion. So  the  therapeutic  value  of  a  circulatory  drug  cannot  be 
measured  by  its  ability  to  raise  arterial  pressure  in  man.  However, 
in  dogs  and  other  laboratory  animals  we  can  inject  toxic  doses 
intravenously,  and  thus  bring  about  a  concentration  of  the  drug 
in  the  blood  which  will  produce  effects  of  sufficient  degree  and 
with  sufficient  rapidity  to  submerge  the  dissipating  influences. 
And  these  give  us  valuable  information  as  to  the  real  sites  and 
modes  of  action  of  a  drug. 

The  Heart. — The  activities  of  the  heart  depend  upon  a  num- 
ber of  things,  viz.,  the  strength  of  contraction  (contractility), 
the  tone  of  the  muscle,  the  recuperative  power,  the  irritability, 
the  conductivity  of  the  stimulus  from  the  pacemaker  to  the  vari- 
ous chambers  of  the  heart,  or  from  one  chamber  to  another,  the 
rate  of  the  beat,  and  the  rhythm. 

The  heart's  action  may  be  affected  by  remedies  directly  or 
indirectly. 

i.  Directly,  by  action  upon  its  muscle  substance.  If  the 
muscle  is  stimulated,  there  is  an  increase  in  its  tone,  in  its  strength 
of  contraction,  and  in  its  irritability;  if  the  muscle  is  depressed, 
there  are  the  opposite  effects. 

2.  Indirectly,  either  through  its  nervous  elements,  through 
changes  in  its  coronary  circulation,  or  through  changes  in  the 
peripheral  resistance. 

The  nervous  elements  of  pharmacologic  importance  are  the 
accelerator  and  the  vagus  systems.  The  accelerators  belong  to 
the  sympathetic  nervous  system.  The  center  is  presumed  to 
have  its  seat  somewhere  in  the  brain,  though  it  has  not  yet  been 
clearly  located.  The  fibers  from  this  terminate  about  certain 
cells  in  the  anterior  horns  of  the  upper  portion  of  the  spinal  cord. 
These  neurons  in  turn  connect  with  the  sympathetic  ganglia,  and 
the  cells  of  these  send  fibers  to  terminate  in  the  heart-wall  at 
the  sinus  node.  The  accelerator  system,  therefore,  is  composed 
of  centers,  nerves,  ganglia,  and  nerve-endings.  The  effects  of 
accelerator  stimulation  are  those  of  direct  muscular  stimulation, 
as  a  rule.  Rothberger  and  Winterberg  (iqio)  have  shown  that 
stimulation  of  the  left  accelerator  results  in  overaction  of  the 


THE   PHYSIOLOGY   OF    THE   CIRCULATION  141 

left  ventricle,  and  stimulation  of  the  right  accelerator  in  over- 
action  of  the  right  ventricle.  But  accelerator  influence  is  not 
always  certain,  and  at  times  accelerator  stimulation  will  result 
merely  in  an  increase  in  contractility  without  change  of  rate, 
or  an  increase  of  rate  without  change  in  contractility  (Howell). 
The  increase  of  rate  is  the  result  of  shortened  diastole. 

The  vagus  system  begins  at  the  vagus  center,  a  collection  of 
cells  on  either  side  of  the  middle  line  in  the  medulla  oblongata, 
and  from  here  the  nerve-fibers  pass  as  the  vagus  nerves  to  groups 
of  cells  in  the  heart-wall  known  as  vagus  ganglia.  From  the  cells 
of  these  ganglia  fibrils  pass  to  the  sinus  node  (the  normal  pace- 
maker) in  the  auricle,  and  to  the  auriculoventricular  junctional 
tissues  at  the  bundle  of  His.  The  vagus  system  comprises,  there- 
fore, the  vagus  centers,  vagus  nerves,  vagus  ganglia,  and  vagus 
nerve-endings.  Its  chief  function,  so  far  as  the  heart  is  con- 
cerned, is  that  of  restraint  or  inhibition,  and  it  is  called  the 
cardio-inhibitory  nerve.  Stimulation  of  any  part  of  the  vagus 
system  results  in  slowing  and  weakening  of  the  heart-beat,  with 
depression  of  conductivity  and  loss  of  tone;  while  depression  of 
the  vagus  system  sets  free  the  heart  and  results  in  increased 
frequency  and  strength  of  the  beat  and  increased  tone.  The 
loss  of  tone  is  manifested  by  greater  relaxation  in  diastole;  the 
diminished  contractility  by  less  complete  contraction  in  systole. 
The  slowing  occurs  essentially  through  a  longer  diastolic  pause. 
Vagus  stimulation  and  depression  are  very  definite  in  their  effects, 
and  so  great  is  the  inhibitory  action  of  the  vagus  that,  under 
powerful  stimulation,  it  can  momentarily  bring  the  heart  to  a 
complete  standstill  in  a  state  of  diastolic  relaxation.  Or  excessive 
vagus  action  may  have'  the  effect  of  partially  or  completely 
checking  the  conduction  of  impulses  from  the  auricle  to  the 
ventricle,  with  the  production  of  heart-block.  The  vagus  action 
is  primarily  on  the  auricle,  and,  so  far  as  known,  is  exerted  upon 
the  ventricle  only  through  the  auriculoventricular  bundle,  except, 
perhaps,  in  a  few  cases  in  which  the  fibers  of  the  right  vagus  pass 
directly  to  the  ventricle  (Cohn). 

Robinson  and  Draper  (191 2),  in  electrocardiagram  studies 
made  during  pressure  of  the  human  vagus  in  the  neck,  found  that 
while  pressure  on  either  vagus  slows  the  rate  of  contraction  and 
retards  conduction  from  auricle  to  ventricle,  yet  pressure  on  the 
right  vagus  has  its  predominating  effect  on  the  rate  of  the  whole 
heart,  while  pressure  on  the  left  vagus  predominates  in  inter- 
ference with  auriculoventricular  conduction. 

The  vagi  and  accelerators  are  thus  in  some  ways  antagonistic, 
and  as  both  are  in  a  state  of  constant  activity,  they  form  a  sensi- 
tive balanced  control-mechanism  which  favors  prompt  response 


142  PHARMACOLOGY  AND   THERAPEUTICS 

to  any  influence.  (Compare  with  the  antagonistic  elements 
governing  the  size  of  the  pupil.)  The  vagus  and  accelerator 
systems  may  be  stimulated  or  depressed  directly  in  any  part  of 
the  system;  or  reflexly,  through  the  center,  by  afferent  impulses 
coming  from  other  parts  of  the  body. 

Resistance. — Up  to  its  limit  of  power,  a  heart  will  beat  more 
slowly  and  more  strongly  in  response  to  increased  peripheral 
resistance;  but  if  the  resistance  is  beyond  the  cardiac  power, 
the  result  is  weakness  and  dilatation  and  cardiac  failure. 

Coronary  Circulation. — Other  things  being  equal,  slowing 
of  the  heart  means  improved  supply  of  coronary  blood,  resulting 
in  better  nutrition  and  better  recuperative  power.  It  has  been 
demonstrated  by  Stewart  and  Pike  (1910)  that  the  heart  will  not 
continue  beating  unless  there  is  a  certian  intracoronary  pressure. 

The  time  of  filling  of  the  heart,  i.  e.,  the  diastole  proper,  de- 
pends upon  the  venous  pressure,  and  is  usually  not  much  greater 
than  the  time  of  systole.  The  remainder  of  the  diastolic  pause, 
i.  e.,  the  diastasis,  is  the  period  during  which  food  and  oxygen 
reach  the  heart  through  the  coronary  arteries  and  during  which 
the  heart  recuperates.  If  the  period  of  diastasis  is  shortened, 
the  heart  beats  more  frequently,  and  its  output  per  minute  is 
increased.  But  if  the  shortening  of  the  diastasis  is  too  great, 
or  if  there  is  no  diastasis,  the  heart  soon  fails  for  lack  of  a  period 
of  nutrition  and  rest.  The  maximum  output  occurs  when  the 
period  of  diastasis  is  just  abolished,  but  under  such  conditions 
the  heart  cannot  long  maintain  its  efficiency.  On  the  other 
hand,  if  the  period  of  diastasis  is  too  prolonged,  the  heart  beats 
so  few  times  in  a  minute  that  it  cannot  maintain  adequate 
arterial  pressure.  Thus  it  is  evident  that  failure  of  the  circula- 
tion may  result  from  too  few  beats  per  minute  or  from  too  many 
beats.  And  it  may  be  assumed  that  for  each  heart  there  is  an 
optimum  rate,  which  is  the  rate  that  gives  the  greatest  number  of 
beats  consistent  with  a  proper  resting  period.  This  optimum 
rate  is  neither  the  maximum  rate  nor  that  which  allows  the 
greatest  output  of  blood;  so  that  the  effect  on  the  rate  of  the 
heart  is  not  the  criterion  of  efficiency  for  a  circulatory  drug. 

Regardless  of  which  control  mechanism  is  utilized,  the  heart's 
action  can  practically  be  modified  as  regards  its  rhythm,  its 
rate,  its  contractility,  its  tone,  its  irritability,  and  its  conductivity. 
The  rhythm  is  either  regular,  irregular,  or  intermittent,  and  may 
be  influenced  by  changes  in  irritability  and  conductivity.  If  the 
rate  is  changed,  it  must  be  either  slower  or  faster;  if  the  contrac- 
tility is  changed,  it  must  be  either  weaker  or  stronger.  If  there 
is  an  alteration  in  tone,  the  degree  of  relaxation  in  diastole  must 
be  either  greater  or  less. 


THE   PHYSIOLOGY   OF   THE   CIRCULATION  1 43 

The  Vessels. — The  Arteries. — Changes  in  the  caliber  of  the 
arterioles  may  be  local,  affecting  the  blood-supply  of  only  one 
or  two  organs,  or  may  be  general,  affecting  general  arterial  pres- 
sure. The  caliber  is  determined  by  the  activity  of  the  arterial 
muscles,  which,  by  their  contraction  narrow  the  lumen  of  the 
artery,  and  by  their  relaxation  widen  it. 

These  muscles  may  act  as  the  result  of  direct  stimulation  or 
depression,  or  in  response  to  impulses  received  through  the  vaso- 
motor nerves.  Of  these  vasomotor  nerves  there  are  two  sets, 
the  vasoconstrictors  and  the  vasodilators,  each  set  consisting  of 
center,  nerves,  ganglia,  and  the  nerve-endings  in  the  arterial 
muscles.  The  vasoconstrictor  centers  are  masses  of  cells  situated 
on  both  sides  of  the  middle  line  in  the  medulla  oblongata;  the 
vasodilator  centers  are  scattered  masses  of  cells  in  various  parts 
of  the  central  nervous  system.  The  arterial  muscles  are  in  a 
constant  state  of  contraction  or  tone,  which  enables  them  to  resist 
the  bursting  pressure  of  the  fluid  within;  and  this  resistance 
tone,  though  insured  to  a  slight  extent  by  the  inherent  nature  of 
muscle  which  makes  it  contract  in  response  to  a  demand  put 
upon  it,  is  due  in  very  large  measure  to  the  continuous  reception 
of  subminimal  impulses  from  the  vasoconstrictor  center.  Thus 
there  is  a  certain  amount  of  contraction  or  tone  normally  present 
in  the  arteries,  and  when  the  vasoconstrictor  centers,  ganglia, 
or  nerve-endings  are  depressed  by  drugs,  this  tone  is  lowered  and 
the  arteries  dilate. 

The  vasodilators  differ  from  the  vasoconstrictors,  for,  in  the 
first  place,  they  do  not  act  continuously,  but  only  under  special 
circumstances;  and,  secondly,  they  produce  dilatation  only  by 
inhibiting  the  contractile  impulses,  for  there  are  no  dilating 
muscles  in  the  arteries. 

Both  the  vasoconstrictor  and  the  vasodilator  nerves  belong 
to  the  sympathetic  system.  When  both  sets  are  stimulated  to- 
gether, the  vasoconstrictor  effect  prevails;  but  under  excessive 
or  prolonged  stimulation  the  vasoconstrictor  is  the  first  to  show 
exhaustion,  so  that  the  constriction  may  be  followed  by  wide 
dilatation,  even  the  intrinsic  tone  of  the  muscle-fibers  being 
probably  somewhat  inhibited. 

Like  the  vagus  and  accelerator  mechanisms,  the  vasomotor 
may  be  affected  by  remedies  acting  directly  upon  any  part  of  the 
vasomotor  system,  viz.,  center,  nerves,  ganglia,  or  nerve-endings; 
and  they  may  also  be  affected  reflexly  by  afferent  impulses  com- 
ing to  the  centers  from  other  parts  of  the  body. 

Besides  the  muscle  itself  and  the  vasomotor  nervous  mech- 
anisms, the  receptive  substance  at  the  neuromuscular  junction  has 
specific  properties,  and  may  be  the  site  of  action  of  a  drug. 


144  PHARMACOLOGY   AND   THERAPEUTICS 

Summary. — The  arteries  may  be  contracted  by: 
i.  Direct  stimulation  of  their  muscle-fibers. 
2.  Direct   or   reflex   stimulation   of   the   vasoconstrictor 
nervous  mechanism,  or  the  neuromuscular  junction. 

The  arteries  may  be  dilated  by: 

i.  Direct  depression  of  their  muscle-fibers. 

2.  Direct    or    reflex    depression    of    the    vasoconstrictor 
nervous  mechanism. 

3.  Direct  or  reflex  stimulation  of  the  vasodilator  mechan- 
ism. 

Some  of  the  arteries  do  not  have  vasoconstrictor  nerves. 
At  least,  nerves  connected  with  the  vasoconstrictor  center  have 
not  been  demonstrated  in  the  coronary  arteries,  those  of  the 
brain,  and  those  of  the  lungs.  (See  Howell.)  These  arteries, 
however,  maintain  their  intrinsic  tone. 

The  blood-supply  of  the  heart  is  somewhat  intermittent,  and 
is  dependent  upon  a  proper  diastolic  pause,  for  during  the  greater 
part  of  systole  the  blood  is  squeezed  out  of  the  coronaries,  while 
during  the  diastolic  pause  the  coronaries  refill  from  the  aorta  and 
make  an  active  circulation  in  the  relaxed  heart.  Dilatation  of 
the  coronaries  is  frequently  brought  about  by  drugs  that  con- 
strict other  arteries.  In  the  brain  the  supply  of  the  blood  is 
largely  determined  by  the  rise  and  fall  of  general  arterial  pres- 
sure, plus  the  influence  of  gravity.  Of  the  pulmonary  circula- 
tion, we  shall  speak  later. 

The  caliber  of  the  cutaneous  arterioles  is  under  a  sensitive  con- 
trol mechanism  different  from  that  of  the  other  arterioles  of  the 
body,  so  that  their  dilatation  and  contraction  frequently  take 
place  independently  of  the  general  arteriole  system,  as  in  blush- 
ing. They  are  weak  arteries,  however,  and  regularly  tend  to  be 
somewhat  dilated  when  general  arterial  pressure  is  high. 

The  veins  also  contain  muscles,  but  their  contraction  and 
dilatation  seem  to  be  of  little  moment  in  pharmacology.  The 
large  veins,  even  the  portal  vein,  as  demonstrated  by  Burton- 
Opitz,  are  scarcely  if  at  all  influenced  through  vasomotor  nerves. 
The  venous  system,  however,  forms  an  enormous  reservoir  for 
blood,  so  that  by  the  accumulation  of  blood  in  the  veins  the 
arterial  system  may  be  readily  depleted.  Venous  pressure 
varies  considerably,  that  in  the  superior  cava  being  alternately 
negative  and  positive,  and  that  in  the  inferior  cava  constantly 
positive  and  sometimes  as  high  as  50  or  60  mm.  of  mercury.  It 
must  be  remembered  that  the  period  of  filling  of  the  ventricle  is 
shortened  if  the  venous  pressure  is  high,  that  during  the  period  of 
diastasis  the  venous  onflow  in  the  large  veins  is  stopped,  and  that 
during  auricular  systole  there  is  some  reflux  into  the  great  veins. 


THE    PHYSIOLOGY   OF   THE   CIRCULATION 


145 


The  capillaries  have  no  muscles,  and  dilate  or  contract 
mechanically  as  more  or  less  blood  is  forced  into  them.  It  is 
their  function  to  serve  as  a  membranous  medium  of  exchange 
between  the  blood  and  the  tissue-fluids,  in  both  directions. 

Arterial  Pressure. — The  gross  factors  which  go  to  maintain 
arterial  pressure  are  four  in  number,  viz.,  the  arteriole  or  periph- 
eral resistance,  the  heart's  output  in  a  given  time,  the  volume  of 
blood  in  the  arteries,  and  the  viscosity  of  the  blood. 

The  pressure  may  be  lowered  by  general  dilatation  of  the 
arterioles,  by  decrease  in  the  heart's  output,  by  loss  of  blood  or 
the  fluid  of  the  blood,  and  slightly  by  a  decrease  in  viscosity. 
It  may  be  raised  by  general  contraction  of  the  arterioles,  by  in- 
crease in  the  output  of  the  heart,  by  the  addition  of  fluid  to  the 
blood,  and  by  an  increase  in  viscosity. 

The  most  important  regulators  of  arterial  pressure  are  the 
arterioles,  but  even  if  the  arterioles  remain  contracted,  pressure 
cannot  be  maintained  if  the  heart  gives  out  or  if  there  is  much 
loss  of  blood. 

Of  the  arterioles,  those  of  the  splanchnic  areas  have  most  to 
do  with  the  regulation  of  arterial  pressure.  They  are  strongly 
muscular,  are  abundantly  supplied  with  nerves  so  that  they  are 
readily  influenced,  and  have,  when  dilated,  an  enormous  capacity. 
Indeed,  when  these  arteries  are  much  relaxed,  so  much  blood 
passes  into  them  that  the  brain  may  be  depleted,  with  fainting 
or  even  death  as  the  result,  so  that  a  person  may  be  said  to  bleed 
into  his  own  splanchnic  arteries.  On  the  contrary,  they  may  be 
so  strongly  contracted  that  the  weaker  arteries  of  the  limbs  and 
skin  are  forced  to  dilate  to  accommodate  the  blood. 

It  is  to  be  noted  that,  so  far  as  life  is  concerned,  the  main- 
tenance of  adequate  cerebral  'and  coronary  circulation  is  the 
essential,  for  upon  these  depends  the  activity  of  the  vital  centers 
in  the  medulla  and  of  the  heart.  Many  times  it  is  in  response  to 
the  needs  of  the  vital  centers  that  physiologic  changes  in  the 
caliber  of  the  arteries  take  place.  The  needs  of  other  parts  of 
the  body,  such  as  the  kidneys,  may  also  greatly  influence  the 
general  arterial  pressure.  Hence  reduction  of  what  seems  ab- 
normally high  arterial  pressure  may  result  in  a  failure  of  these 
organs  to  functionate.  (For  a  resume  of  theories  relating  to 
high  pressure  in  kidney  disease  see  Janeway's  Harvey  Society 
Lecture,  1913.) 

The  Pulmonary  Circulation. — The  pulmonary  arteries  have 
no  vasoconstrictor  nerves,  but  maintain  an  intrinsic  muscular 
tone  of  moderate  degree.  They  transmit  just  as  much  blood  as 
the  systemic  arteries,  for  since  the  system  is  essentially  a  closed 
•one,  just  as  much  blood  must  be  pumped  by  the  right  ventricle 


146  PHARMACOLOGY  AND  THERAPEUTICS 

as  by  the  left  ventricle,  minus  a  slight  loss  from  the  lung  capil- 
laries. But  the  thin  walls  and  feebler  muscle  of  the  right  ven- 
tricle show  that  less  power  is  required  in  the  transmission  of  the 
blood,  and  it  is  evident  that  the  pulmonary  arteries  give  little 
resistance  to  the  blood-flow.  It  is  estimated  that  the  normal  pul- 
monary arterial  pressure  is  only  one-seventh  to  one- third  that 
in  the  aorta. 

In  certain  cardiac  affections,  however,  where  there  is  back 
pressure  on  the  pulmonary  circulation,  as  in  obstruction  at  the 
mitral  valve,  the  right  ventricle  becomes  thick  and  strong  and 
its  cavity  larger,  and  the  pulmonary  pressure  may  rise  so  high 
as  to  rupture  one  or  more  of  the  smaller  arteries  of  the  lungs. 
Such  a  pressure  is  mechanical,  depending  upon  two  factors,  viz., 
increased  output  of  the  right  ventricle  and  obstruction  to  the 
onward  flow  of  blood  in  the  left  heart. 

So  far  as  we  know,  all  drugs  which  affect  the  left  ventricle 
will  proportionately  affect  the  right  ventricle;  and  no  difference 
has  been -noted  except  in  those  rare  cases  in  which,  through 
organic  narrowing  or  impairment  of  contractility  in  one  coronary, 
the  other  only  is  affected  by  the  drug.  The  degree  of  filling  of 
the  right  ventricle  depends  upon  the  amount  of  venous  pressure 
versus  the  tone  of  the  heart  muscle.  The  rapidity  of  filling 
increases  with  the  venous  pressure  (Hirschf elder). 

Compensation. — A  term  much  employed  in  connection  with 
disturbances  of  the  circulation  is  "compensation,"  which  refers 
to  the  ability  of  the  heart  to  maintain  arterial  pressure  in  spite 
of  some  condition  or  lesion  which  tends  to  make  the  arterial 
pressure  low.  It  is  the  ability  of  the  heart  to  compensate  for 
some  leakage  or  other  adverse  condition.  We  speak  of  the  lack 
or  failure  of  compensation  when  the  heart  is  unable  to  maintain 
adequate  arterial  pressure.  The  effects  of  failure  of  compensa- 
tion are:  (1)  General  venous  and  pulmonary  engorgement,  with 
lymphatic  damming  up  and  a  tendency  to  edema  and  dropsy. 
(2)  Diminished  supply  of  blood  to  the  organs.  (3)  Poor  aera- 
tion of  the  blood  on  account  of  the  sluggish  pulmonary  circula- 
tion. The  symptoms  are:  Labored  breathing,  inability  to  He 
flat,  weak  and  dilated  heart,  rapid  pulse,  sluggish  peripheral 
circulation  with  cold  extremities,  cyanosis,  and  perhaps  edema 
or  dropsy. 

Ordinarily,  when  a  lesion,  e.  g.,  a  defective  valve,  would  tend 
to  interfere  with  the  heart's  ability,  there  is  a  natural  compen- 
satory hypertrophy  of  the  muscle  and  a  compensatory  enlarge- 
ment of  one  or  other  of  its  cavities,  which  is  spoken  of  as  "dilata- 
tion"; so  that  in  spite  of  quite  a  marked  lesion  of  the  heart, 
compensation  may  be  maintained.     Thus  if  there  is  a  lesion  of 


THE    GENERAL    CIRCULATORY    STIMULANTS  147 

the  mitral  valve  which  permits  leakage,  then  at  each  systole 
some  of  the  blood  from  the  ventricle  is  forced  back  through  the 
leaking  valve  into  the  auricle,  instead  of  forward  into  the  sys- 
temic arteries.  In  consequence,  the  heart  would  not  be  able  to 
keep  up  the  systemic  circulation  were  it  not  for  the  fact  that  in 
response  to  requirement  the  cavity  of  the  ventricle  becomes 
more  capacious,  and  the  muscular  walls  become  hypertrophied, 
so  that  the  heart  can  pump  more  blood  at  each  systole.  It  thus 
provides  for  the  needs  of  the  systemic  circulation  in  addition  to 
the  leakage.  In  other  words,  by  dilatation  and  hypertrophy 
the  heart  compensates  for  the  loss  by  leakage. 

Sooner  or  later,  however,  the  lesion  extends  beyond  any 
power  of  natural  compensation;  or  for  some  other  reason,  usually 
fibrillation  of  the  auricle,  the  muscle  fails,  and  then  there  is 
failure  of  compensation.  A  condition  of  threatened  failure  of 
compensation  may  exist  when  the  heart  is  on  the  brink  of  failure, 
but  remains  adequate  so  long  as  special  pains  are  taken  to  pro- 
tect the  body  from  effort.  In  these  cases  there  is  no  reserve 
force,  and  failure  is  constantly  threatened. 

Mackenzie  perhaps  expresses  these  ideas  better  by  assuming 
that  the  power  of  the  heart  may  be  divided  into  a  working  force 
and  a  rest  force.  The  rest  force  is  that  which  meets  the  needs  of 
the  body  at  rest,  while  the  working  force  meets  the  additional 
requirements  when  the  body  is  engaged  in  effort.  The  begin- 
ning of  heart  weakness  would  then  be  evidenced  by  limitation  of 
the  working  force.  It  might  show  by  discomfort  or  distress  in 
performing  some  act  which  formerly  gave  no  distress,  e.g.,  short- 
ness of  breath  on  going  up  stairs,  on  running,  or  on  lifting  a  heavy 
weight.  The  working  force  may  be  encroached  upon  to  any 
degree,  even  to  its  exhaustion,  but  if  the  rest  force  remains,  the 
patient  may  still  maintain  an  adequate  circulation  if  put  to  bed 
and  kept  from  effort.  When  the  rest  force  is  cut  down,  there  is 
serious  failure  of  compensation,  with  the  consequences  as  de- 
tailed above. 

The  General  Circulatory  Stimulants 

Besides  drugs,  various  remedial  measures  are  adopted  in  the 
treatment  of  failing  circulation,  such  as  rest  in  bed,  light,  non- 
fermenting  diet  with  restriction  of  liquids,  the  cold  bath,  the 
Nauheim  bath,  cold  air,  regulated  exercises,  etc. 

The  Nauheim  bath  is  a  saline  bath  in  the  water  of  which  car- 
bon dioxide  is  set  free.  It  tends  to  raise  the  arterial  pressure,  in 
some  cases  to  a  dangerous  degree. 

Cold  Air. — Howland  (191 1)  found  that  in  children  with 
pneumonia,  removal  to  the  cold  outdoor  air  of  winter  sent  the 


148  PHARMACOLOGY  AND  THERAPEUTICS 

pressure  up,  on  the  average,  about  15  mm.  of  mercury.  Hoobler 
(191 2)  found  that  the  blood-pressure  of  tuberculous  children 
gradually  rose  when  they  were  kept  in  the  open  air,  and  fell 
when  they  were  kept  indoors.  Barringer  (191 2),  however, 
reports  no  continued  effects  on  the  pressure  in  adults. 

The  drugs  of  the  class  are:  Digitalis  and  its  allies  (strophan- 
thus,  convallaria,  etc.),  epinephrine,  ammonia,  and  possibly 
camphor.  There  are  a  few  others,  such  as  caffeine,  whose  domi- 
nant actions  place  them  more  properly  in  other  groups. 

DIGITALIS 

Digitalis  (Lat.,  digitalis),  or  foxglove,  is  the  dried  leaves  of 
Digitalis  purpurea  (Fam.  Scrophulariacece).  It  is  an  ornamental 
flower  of  the  gardens,  grows  wild  in  Europe,  Oregon,  and  Aus- 
tralia, and  is  cultivated  for  the  drug  market  in  England  and 
Germany. 

Constituents. — The  active  principles  are  glucosides,  and  are, 
therefore,  subject  to  ready  destruction.  Digitoxin,  which  most 
nearly  represents  the  digitalis  action,  is  practically  insoluble  in 
water,  but  soluble  in  alcohol.  It  is  present  to  the  extent  of 
0.2  to  0.4  per  cent.  Di gitalin,  next  in  importance,  is  slightly 
soluble  in  water,  soluble  in  100  parts  of  diluted  alcohol,  and  read- 
ily in  alcohol.  DigikUein,  of  similar  nature,  is  soluble  in  both 
water  and  alcohol.  Under  the  influence  of  heat  or  acids,  or 
when  kept  some  time  in  aqueous  solution,  as  in  the  infusion, 
these  glucosides  tend  to  decompose,  and  may  form  toxiresins 
which  have  a  central  convulsant  action. 

In  addition  to  these  active  principles,  digitalis  contains 
digitonin,  a  saponin  body  which  foams  with  water  and  possesses 
the  peculiar  property  of  holding  the  otherwise  insoluble  active 
principles  in  solution  in  water.  It  is  on  account  of  this  that  the 
infusion  of  digitalis,  an  aqueous  preparation,  represents  the 
activity  of  the  drug.  Digitonin,  administered  intravenously, 
is  a  physiologic  antagonist  of  digitoxin;  but  it  is  not  absorbable 
from  the  alimentary  tract.  It  crystallizes  from  solutions  in 
alcohol  of  over  85  per  cent,  strength.  Besides  these  principles, 
digitalis  contains  an  acrid,  nauseating  substance,  digitalosmin, 
and  free  oil. 

Preparations  and  Doses. — Official. — Digitalis,  dose,  1  grain 
(0.06  gm.).  Extract,  A  grain  (0.01  gm.).  Fluidextract,  1  minim 
(0.06  c.c).  Tincture,  10  per  cent.,  10  minims  (0.6  c.c).  Infu- 
sion, 1.5  per  cent.,  1  dram  (4  c.c).  The  infusion  of  the  U.  S.  P.  is 
made  with  hot  water,  but  contains  10  per  cent,  of  alcohol  as  pre- 
servative. The  doses  above  may  be  increased  up  to  four  times 
as  much  in  serious  cases. 


DIGITALIS  149 

Unofficial. — Digitoxin,  dose,  T^-g-  grain  (0.0005  gm-)>  is  too 
irritating  for  hypodermatic  use. 

Digitalin,  dose,  TV  grain  (0.006  gm.),  is  moderately  irritating, 
but  can  be  used  hypodermatically. 

Digalen,  made  according  to  Cloetta's  formula,  is  a  proprietary 
remedy  which,  it  is  claimed,  contains  ■j'k's  grain  (0.3  mg.)  of 
digitoxin  in  each  15  minims  (1  ex.),  the  solvent  being  alcohol, 
glycerin,  and  water.  A  number  of  investigators  believe  that 
this  is  not  digitoxin,  but  probably  digitalein.  It  is  moderately 
irritating,  but  has  been  used  intravenously.  Laboratory  experi- 
ments show  its  action  to  be  very  variable. 

Digipuratum,  made  according  to  Gottlieb's  formula,  is  an 
extract  freed  from  digitonin  and  most  of  the  extractive  matter, 
and  mixed  with  sugar  of  milk  to  form  a  powder  of  the  same 
strength  as  digitalis  leaves.  Worth  Hale  and  others  have  found 
it  a  good  preparation.  In  our  own  experience  it  is  exceedingly 
uniform.  It  is  marketed  in  tablet  and  liquid  form.  The  tablets 
are  equivalent  to  i}4  grains  (0.1  gm.)  of  digitalis.  The  liquid 
form  is  for  intravenous  or  hypodermatic  use,  15  minims  (1  c.c.) 
being  equivalent  to  i)4  grains  (0.1  gm.)  of  digitalis. 

There  are  many  other  unofficial  preparations  on  the  market. 
A  serious  difficulty  with  all  digitalis  preparations  is  their  tendency 
to  deteriorate. 

In  a  comparative  test  by  Edmunds  the  infusion  and  the  tinc- 
ture were  found  of  equal  efficiency  when  given  in  doses  corre- 
sponding with  the  amount  of  digitalis  used  in  their  making. 
Focke  (1909),  however,  found  the  infusion  regularly  about  20 
per  cent,  weaker  than  the  powdered  leaves,  and  because  of  the 
method  of  its  manufacture,  it  is  probable  that  this  is  usually 
the  case.  The  tincture  and  infusion  are  the  best  official  prepara- 
tions. The  author  has  frequently  seen  the  infusion  prescribed  in 
half-ounce  doses.  This  is  equivalent  to  36  minims  of  the  tinc- 
ture, and  is  a  large  dose;  but  it  is  probable  that  in  serious  cases 
the  best  results  are  obtained  only  when  such  very  large  amounts 
are  employed  at  the  outset.  The  effects  of  these  large  doses  of 
the  infusion  have  frequently  been  compared  with  those  from 
small  doses  of  the  tincture,  naturally  to  the  disadvantage  of  the 
latter. 

The  fluidextract  is  a  concentrated  preparation  with  a  small 
dose,  and  to  its  use  there  are  the  following  objections:  (1)  On 
account  of  the  small  amount  of  solvent,  there  is  uncertainty  that 
all  the  active  principles  of  the  drug  are  extracted  in  the  prepara- 
tion; (2)  precipitation  is  likely  from  inability  of  the  solvent  to 
hold  so  much  dissolved  matter;  (3)  deterioration  is  more  likely, 
as  the  solvent  is  insufficient  to  act  as  a  preservative;  (4)  very 


150  PHARMACOLOGY  AND  THERAPEUTICS 

slight  evaporation  materially  changes  the  strength  of  the  prep- 
aration; and  (5)  owing  to  the  smallness  of  the  dose,  it  is  difficult 
to  grade  the  dosage.  As  a  matter  of  fact,  Worth  Hale  had 
digitalis  leaves  made  into  tincture  and  fluidextract,  and  found 
the  latter  only  about  three  times  as  strong  as  the  former,  instead 
of  ten  times,  as  it  should  be.  Assays  of  commercial  prepara- 
tions have  given  similar  findings.  Hence  the  fluidextract  should 
be  abandoned  from  use. 

Digitalis  Allies. — There  are  some  other  drugs  with  effects  of 
the  digitalis  kind,  and  the  whole  group  is  known  as  the  digitalis 
group,  or  the  digitalis  series.  The  members  of  the  group  that 
are  employed  as  circulatory  stimulants  are  digitalis,  convallaria, 
strophanthus,  squill,  apocynum,  adonis,  and  their  active  prin- 
ciples, and  the  glucosides,  ouabain  and  hellebore'in.  Several 
other  drugs,  such  as  oleander,  cereus  grandiflorus,  and  erythro- 
phleum  (sassy  bark),  are  reputed  to  have  some  of  the  actions  of 
digitalis,  but  have  not  come  into  general  use. 

Strophanthus  (strophanthus),  "the  ripe  seed  of  Strophanthus 
Kombe  (Fam.  A pocynacece) ,  deprived  of  its  long  awn,"  comes 
from  a  woody  climbing  plant  of  eastern  Africa. 

Constituents. — The  seeds  contain  from  1  to  3  per  cent,  of  an 
active  body,  strophanthin.  This  is  either  a  single  glucoside 
(methyl-ouabain)  or  a  mixture  of  glucosides,  and  is  soluble  in 
water  and  alcohol.  The  seeds  of  a  number  of  species  of  strophan- 
thus come  upon  the  market,  but  only  two,  S.  Kombe  and  S.  his- 
pidus,  have  been  satisfactorily  studied.  Strophanthus  hispidus 
contains  pseudo-stro phanthin,  which,  according  to  Pfaff,  is  more 
poisonous  to  the  heart  muscle  than  strophanthin.  Strophan- 
thus is  relatively  much  more  toxic  to  the  muscle  than  digitalis, 
as  shown  below. 

Preparations  and  Doses. — Strophanthus,  }-4  grain  (0.03  gm.). 
Tincture,  10  per  cent.,  5  minims  (0.3  c.c).  Strophanthin,  -^w 
grain  (0.0003  gm-)- 

Convallaria  (lily-of- the- valley)  is  "  the  dried  rhizome  and 
roots  of  Convallaria  majalis  (Fam.  Liliacece)^  the  common 
lily-of-the-valley,  which  grows  wild  in  Europe,  Asia,  and  the 
Allegheny  Mountains.  The  drug  contains  the  active  glucoside, 
convallamarin,  and  a  saponin-like  glucoside  of  the  digitonin  type, 
convallarin.  The  fluidextract  is  the  only  official  preparation, 
dose,  10  minims  (0.6  c.c).  Some  of  the  fluidextract  on  the 
market  is  made  from  the  leaves,  instead  of  from  the  rhizome  and 
roots  as  the  Pharmacopoeia  directs.  Convallaria  is  relatively 
much  more  poisonous  than  digitalis,  as  shown  below. 

Squill  (scilla),  dose  i}4  grains  (0.1  gm.),  has  for  prepara- 
tions the  fluidextract,  the  10  per  cent,  tincture,  the  10  per  cent. 


DIGITALIS  151 

vinegar  (acetum),  and  the  three  expectorant  mixtures,  syrup  of 
squill,  which  contains  45  per  cent,  of  the  vinegar,  the  compound 
syrup  of  squill,  which  contains  8  per  cent,  of  the  fluidextract,  and 
the  National  Formulary  preparation,  mistura  pectoralis  (Stokes' 
expectorant),  which  contains  3.5  per  cent,  of  the  fluidextract. 
The  expectorant  effect  is  probably  the  result  of  a  nauseant  action 
in  the  stomach.  It  contains  the  glucosides,  scillam  and  scilli- 
toxin,  bodies  of  uncertain  composition. 

Apocynum  (dogbane),  dose,  15  grains  (1  c.c),  has  an  official 
fluidextract.     It  contains  the  glucosides,  apocynin  and  apocynein. 

Adonis  vernalis  is  not  official.  Its  dose  is  10  grains  (0.6  gm.), 
and  it  is  employed  in  the  form  of  fluidextract  or  infusion.  Its 
active  glucoside,  adonidin,  may  also  be  used  in  dose  of  y1^  grain 
(0.006  gm.). 

Ouabain,  known  as  "crystalline  gratus  strophanthin,"  is  a 
stable  crystalline  glucoside  of  great  activity.  Its  lethal  dose  is 
that  of  digitoxin.  Because  of  its  stability  it  has  been  suggested 
as  a  standard  for  physiologic  comparison. 

The  Standardization  and  Permanency  of  Preparations. — 
Edmunds,  by  physiologic  assay  of  16  different  commercial 
samples  of  the  tincture  of  digitalis,  found  that  the  dose  necessary 
to  produce  systolic  standstill  in  a  20  gm.  frog  varied  from  0.08  c.c. 
of  the  strongest  to  0.29  c.c.  of  the  weakest.  A  tincture  made 
from  one  batch  of  drug  might  thus  have  three  or  four  times  the 
strength  of  one  made  from  another  batch  of  drug,  and  the  cor- 
rect dose  of  one  would  be  the  wrong  dose  of  the  other.  Haynes, 
Hale,  and  others  have  found  similar  variation.  In  addition,  all 
the  preparations  slowly  deteriorate  on  keeping.  It  is  because 
of  these  things  that  some  reliable  method  of  assay  is  absolutely 
necessary,  and  a  limit  of  age  established  beyond  which  the 
preparation  should  not  be  used. 

Both  pharmaceutic  and  physiologic  assay  processes  have 
been  employed  by  the  manufacturers.  The  pharmaceutic  assay 
consists  of  the  estimation  of  the  amount  of  digitoxin  present;  but 
this  assay  is  inadequate,  for  the  amount  of  digitoxin  has  been 
found  to  give  no  fair  idea  of  the  drug's  activity.  There  are 
several  physiologic  assay  processes,  perhaps  the  best  being  the 
comparison  with  a  standard  preparation  of  the  amount  required 
to  bring  a  frog's  heart  to  systolic  standstill.  The  standard  is 
0.0007  gm-  digitalis  per  gm.  of  body  weight.  The  frogs  must  be 
of  the  same  species,  sex,  weight,  and  must  be  tested  at  the  same 
time.  Unfortunately,  this  method  is  not  of  use  for  the  compari- 
son of  different  drugs,  but  only  for  comparison  of  different  prepa- 
rations of  one  drug.     If  ouabain  is  employed  as  the  standard, 


152  PHARMACOLOGY  AND  THERAPEUTICS 

"accurate  results  may  be  obtained  without  reference  to  season, 
age,  sex,  temperature,  conditions  or  species  of  frog  used"  (Hale). 

As  to  the  reliability  of  preparations  of  strophanthus  we  have 
some  evidence.  Hatcher  tested  old  and  new  tinctures  of  stro- 
phanthus, and  tinctures  made  from  recently  imported  seeds  and 
from  very  old  seeds,  and  reported  them  as  being  fairly  uniform. 
He  claims  that,  unlike  digitalis,  strophanthus  does  not  deterio- 
rate with  age.  Houghton  reported  that  the  tinctures  of  stro- 
phanthus on  the  market  varied  so  that  the  strongest  were  three 
times  as  strong  as  the  weakest;  and  Edmunds,  in  testing  five 
specimens  of  the  tincture  by  their  power  to  bring  a  20  gm.  frog's 
heart  to  systolic  standstill,  found  the  strongest  four  times  as 
strong  as  the  weakest.  (It  took  0.0012  c.c.  of  the  strongest  and 
0.005  c.c.  of  the  weakest.)  So  the  possibility  of  great  difference 
in  the  strengths  of  preparations  must  be  borne  in  mind,  and 
reliable  assays  taken  advantage  of  when  possible.  Houghton 
has  also  reported  that  he  has  found  wide  variation  in  the  activity 
of  commercial  strophanthins,  one  sample  being  90  times  as  fatal 
as  another. 

Houghton's  table  of  comparisons  of  the  minimum  fatal  dose 
of  official  preparations,  as  tested  by  the  frog  method,  is  as  follows: 

Digitalis Fluidextract 0.0015  c.c. 

Tincture 0.015  c.c. 

Extract 0.0005  gm. 

Strophanthus Tincture 0.000083  c.c. 

Convallaria Fluidextract 0.00025  c.c. 

Squill Fluidextract 0.0012  c.c. 

This  would  make  the  relative  toxicity  of  equal  amounts  of  the 
drug  as  follows:  digitalis,  i:  strophanthus,  18.5;  convallaria,  6; 
squill,  1.2.  Hatcher's  figures  from  equal  amounts  by  intravenous 
dosage  in  the  dog  are:  digitalis,  i;  convallaria,  i;  apocynum, 
\;  squill,  5V  These  figures  do  not  show  the  relative  clinical 
efficiency,  however,  but  only  their  relative  toxicity;  and  the 
clinical  doses  bear  no  relation  to  the  lethal  doses.  In  proportion 
to  the  therapeutic  dose,  except  by  intravenous  administration, 
digitalis  is  the  least  toxic  of  them  all. 

Worth  Hale's  comparison  of  active  principles  by  the  frog 
method  is  as  follows:  The  minimum  fatal  dose  of  strophanthin 
is  o.ooooon;  of  convallamarin,  0.00000475;  of  digitoxin, 
0.0000085;  of  French  digitalin,  0.000013;  of  digitalein,  0.000024; 
of  German  digitalin,  0.00007.  This  would  make  the  relative 
toxicity  of  equal  amounts  as  follows:  digitoxin,  1;  strophan- 
thin, 8;  convallamarin,  2;  French  digitalin,  f;  digitalein,  \; 
German  digitalin,  \  approximately.     Hatcher's  comparison  of 


DIGITALIS 


*S3 


toxicities  in  cats  by  intravenous  administration  is:  ouabain,  4; 
digi toxin,  1;  scillitoxin,  1;  true  digitalin,  y4;  convallamarin,  ,:4; 
digitalein,  \\  German  digitalin,  \. 

Pharmacologic  Action. — Local  Action. — Digitalis  has  no 
effect  on  the  unbroken  skin,  but  to  mucous  membranes  and  sub- 
cutaneous tissues  is  irritant.  When  administered  hypodermati- 
cally,  it  causes  pain  at  the  site  of  injection,  and  through  its  irritant 
properties  may  cause  destruction  of  tissue,  with  the  formation 
of  either  a  slough  or  a  sterile  abscess  (sterile  because  not  due  to 
pathogenic  bacteria).  In  a  sick  patient  a  number  of  such 
irritative  areas  are  sufficient  to  cause  fever  and  depressing 
reflexes,  or  at  least  much  discomfort,  so  that  the  hypodermatic 
use  of  digitalis  preparations  is  to  be  avoided  when  possible.  Of 
the  active  principles,  digitalein  is  the  least  irritating,  digitoxin 
the  most  irritating. 

Alimentary  Tract. — The  taste  is  bitter  and  unpleasant. 
Because  of  the  local  irritant  effect  in  the  stomach,  nausea  or  even 
vomiting  may  result.  But  in  practice,  this  nausea  and  vomiting 
usually  come  on  only  after  the  patient  has  been  taking  digitalis 
for  several  days;  and  this  is  because  their  chief  cause  is  not  the 
irritation  of  the  stomach,  but  stimulation  of  the  vomiting  center 
after  the  drug  has  become  absorbed.  This  stimulation  in- 
creases until  the  center  becomes  so  sensitive  that  the  slight 
irritation  of  each  subsequent  dose  results  in  nausea  or  vomiting, 
and  requires  that  the  administration  of  the  drug  be  stopped. 
This  undesirable  effect  is  thus  largely  central,  and  it  occurs  from 
doses  administered  intravenously,  hypodermatically,  or  by  rectum, 
as  well  as  those  administered  by  mouth.  But  a  sensitive  vomit- 
ing center  makes  the  stomach  highly  susceptible  to  local  irritants, 
hence  doses  by  mouth  are  more  prone  to  produce  vomiting  than 
doses  administered  in  other  ways. 

Upon  the  intestines  there  is  ordinarily  no  effect,  but  some- 
times, probably  either  from  the  local  irritation  of  unabsorbed 
drug  or  from  stimulation  of  the  motor  nerves  of  the  intestines 
(the  vagus  nerves),  or  perhaps  from  muscular  stimulation, 
diarrhea  is  set  up.  Strophanthin  has  been  shown  to  be  a  direct 
stimulant  of  intestinal  muscle. 

Digitalis,  then,  has  decided  effects  upon  the  stomach  and 
intestines,  but  they  are  undesirable  ones.  Worth  Hale  has 
determined  that  in  a  period  of  three  hours  the  acid  of  the  gastric 
juice  invariably  causes  a  diminution  of  from  25  to  35  per  cent,  in 
the  activity  of  the  digitalis  and  strophanthus  glucosides.  He 
recommends  that  to  avoid  this  the  official  preparations  should  be 
neutral;  but  should  be  administered  with  an  alkali,  and  not 
after  meals,  but  later,  when  the  gastric  acidity  is  low. 


154  PHARMACOLOGY   AND    THERAPEUTICS 

Absorption  takes  place  from  the  intestines,  and  since  the  drug 
penetrates  the  tissues  very  slowly,  is  uncertain  in  rate  and  degree. 
Thus  twelve  to  thirty-six  hours,  and  sometimes  several  days, 
elapse  before  the  systemic  action  is  manifest.  After  deep  intra- 
muscular injections  the  effects  follow  more  rapidly;  but  even 
then,  owing  to  the  drug's  slow  diffusibility,  may  not  appear  for 
hours.  In  dogs,  intravenous  toxic  doses  will  produce  a  prompt 
response,  but  in  man  even  intravenous  administration  of  thera- 

i/WVA /\7\A    _A 


Ral'w»X       &AV»u<ua.W<c    jOJfcvillei&er*.. 

<^o^UXYVu/ttU>v.Kgt  byJUtwsbl<j«*M,*us. 

Fig.  S. 

peutic  amounts  may  require  one-half  to  several  hours  for  measur- 
able results. 

Where  the  digitalis  principles  remain  is  not  yet  certain. 
Cloetta  found  no  digitoxin  in  the  heart  muscle  of  rats  and  frogs. 
Hatcher  (1912)  states  that,  after  an  intravenous  injection  of 
a  fatal  dose  in  cats,  ouabain  leaves  the  blood  in  about  three 
minutes.  After  the  injection  of  double  the  lethal  dose  of  digi- 
toxin death  takes  place  in  five  minutes;  and  during  the  adminis- 


DIGITALIS 


155 


tration  of  an  oyerwhelming  dose,  it  takes  place  almost  in- 
stantaneously. Therefore,  the  delayed  therapeutic  action  from 
mouth  doses  hardly  seems  to  be  due  to  failure  of  the  heart  to 
take  up  the  drug,  and  must  be  due  to  delayed  absorption.  Yet 
from  less  than  the  fatal  dose  some  of  the  digitoxin  effect  may 
persist  for  three  or  four  weeks. 

Circulation. — In  a  laboratory  animal  it  is  observed  that  a 
good-sized  dose  of  digitalis  has  profound  effects  upon  the  circu- 
lation.    The   striking  laboratory  effects  are  given  under  Tox- 

nI\J\J\J\T\I\J\J\J  Tik 


A^i^^^^J\^J\ 


3  HuutSlod^.^oaUoA,. 


HaJjuiX 


Fig.  6. 

icology.  In  both  the  laboratory  animal  and  in  man  the  circula- 
tory effects  are  known  to  be  brought  about  through  action  upon 
five  different  structures.  These  structures  are  the  sinus  node, 
the  cardiac  muscle,  the  auriculoventricular  bundle,  the  coronary 
arteries,  and  the  systemic  arteries.  The  following  are  the  effects 
noted  in  man: 

A.  Through  the  Sinus  Node. — This  is  believed  to  be  the 
normal  controller  or  pacemaker  of  the  rate  of  the  heart.  From 
it  impulses  are  given  to  the  auricles  at  more  or  less  regular  inter- 


156  PHARMACOLOGY  AND  THERAPEUTICS 

vals  of  time,  and  normally  at  the  rate  of  about  72  in  a  minute. 
In  response  to  these  impulses  the  auricles  contract  together  and 
are  followed  in  about  one-fifth  of  a  second  by  contraction  of  the 
ventricles  together.  A  rhythm  essentially  under  the  control 
of  sinus  impulses  is  known  as  " normal  rhythm." 

Slowing. — One  effect  of  the  administration  of  digitalis  is  to 
inhibit  or  retard  the  projection  of  impulses  by  the  sinus  node, 
the  result  being  slowing  in  the  rate  of  the  heart.  The  same 
type  of  slowing  is  produced  by  stimulation  of  a  vagus  nerve,  as 
may  be  observed  in  man  by  pressure  on  the  vagus  nerve  in  the 
neck,  or  in  animals  by  electric  stimulation  of  the  peripheral 
segment  of  a  cut  vagus.  Whether  the  slowing  results  from 
electric  or  mechanical  vagus  stimulation  or  from  digitalis,  it  is 
abolished  by  atropine,  which  paralyzes  the  vagus  nerve-endings 
in  the  heart.  Thus  we  have  evidence  that  digitalis  slowing 
may  be  identical  with  that  from  vagus  stimulation. 

Again,  in  an  animal  with  vagus  nerves  cut,  or  in  an  isolated 
heart,  i.  e.,  a  heart  severed  from  all  its  connection  with  the  centers, 
the  digitalis  slowing  is  very  slight.  This  is  evidence  that  the 
essential  slowing  from  digitalis  does  not  come  from  action  on  the 
sinus  node  directly,  but  from  action  on  the  vagus  centers.  In  other 
words,  the  effects  are  vagus  effects,  and  they  are  not  to  any  great 
extent  produced  when  the  heart  is  severed  from  connection  with 
the  vagus  centers.  Therefore  we  have  the  evidence  that,  in  a 
heart  with  normal  rhythm,  digitalis  may  slow  the  rate  by 
stimulating  the  vagus  centers.  There  is  probably  also  a  slight 
stimulating  effect  on  the  ends  of  the  vagus  nerves,  but  this  is  not 
important. 

In  therapeutics  this  type  of  slowing  is  sometimes  a  desirable 
effect;  but  if  the  slowing  becomes  so  marked  that  the  heart  does 
not  beat  frequently  enough  to  maintain  an  efficient  circulation, 
it  is  a  poisonous  effect.  In  certain  conditions,  therapeutic 
amounts  of  digitalis,  sometimes  though  not  invariably,  fail  to 
produce  slowing,  as — (1)  When  the  rate  is  already  normal  or 
slow;  or  (2)  in  old  age;  or  (3)  in  the  rapid  pulse  of  tuberculosis, 
paroxysmal  tachycardia,  and  some  of  the  infectious  fevers.  In 
pneumonia  and  other  similar  conditions  the  toxins  of  the  disease 
may  affect  the  heart  muscle  so  as  to  increase  its  irritability  and 
make  it  resistant  to  vagus  influence.  Hence  absence  of  slowing 
must  not  be  taken  as  an  indication  of  the  drug's  inefficiency. 

In  some  cases  it  is  possible  that  digitalis  causes  complete 
physiologic  standstill  of  both  auricle  and  ventricle  for  a  moment, 
as  is  seen  upon  electric  stimulation  of  a  vagus  nerve,  but  this  has 
not  been  reported  as  a  digitalis  effect  in  man. 

Arhythmia. — Another  effect  of  digitalis  upon  the  sinus  node 


DIGITALIS  157 

is  to  change  its  rhythmic  projection  of  impulses,  so  that  the 
heart-rate  shows  regularly  alternating  short  phases  of  accelera- 
tion and  slowing.  That  is,  the  rate  rhythmically  waxes  and 
wanes,  whether  the  total  rate  is  slowed  or  not.  This  is  also  the 
effect  of  vagus  stimulation,  and  it  is  abolished  by  atropine.  It 
is  known  as  sinus  arhythmia  or  phasic  arhythmia.  During 
forced  inspiration  and  expiration  this  arhythmia  is  physiologic, 
and  may  be  observed  in  most  people,  the  phases  corresponding 
with  the  phases  of  respiration.  But  when  it  results  from  digi- 
talis it  sometimes  has  no  relation  to  the  respiratory  rhythm;  it 
is  then  an  indication  of  beginning  poisoning. 

Summary. — Through  the  sinus  node  the  digitalis  effects  are 
either  slowing  of  the  rate  or  sinus  arhythmia  or  both,  or  pos- 
sibly momentary  standstill.  They  result  from  vagus  stimula- 
tion. 

B.  The  Cardiac  Muscle. — The  striking  properties  of  the 
heart  muscle,  as  viewed  pharmacologically,  are  tonicity,  con- 
tractility, and  irritability  (excita- 
bility). Tonicity  of  muscle  is  its 
property  of  maintaining,  during  its 
resting  period,  a  state  of  partial 
contraction  or  incomplete  relaxa- 
tion, i.  e.,  a  state  of  tone,  which 
keeps  it  in  readiness  to  respond 
promptly  when  a  stimulus  comes.  Fig.  1_D  capacity  at  end 

In  a  hollow  organ  like  the  heart  the         of  diastole;    S,  capacity  at  end  of 
tone  gives  it  resistance  to  a  burst-       systole, 
ing  pressure  during  the  period  when 

the  organ  is  not  actively  contracting.  It  is  measured  by  the  de- 
gree of  relaxation  in  diastole.  Contractility  is  the  power  of  con- 
traction in  systole.  It  is  measured  by  the  size  of  the  heart  at 
the  end  of  systole.  Tonicity  differs  from  contractility,  which  has 
to  do  with  the  active  contraction,  and  from  irritability,  which 
deals  with  sensitiveness  to  stimuli. 

1.  Contractility  and  Tonicity. — In  a  heart  whose  contrac- 
tility and  tonicity  are  below  the  normal,  the  ventricular  chambers 
are  dilated  and  weak,  so  that  in  diastole  the  muscle  is  stretched 
beyond  the  normal  by  the  venous  inflow,  and  in  systole  con- 
tracts feebly.     The  result  is  a  decreased  output  of  blood. 

If  we  take  two  concentric  spheres  and  let  one  represent  the 
capacity  of  the  heart  during  the  resting  period  of  diastole,  and 
the  other  the  capacity  at  the  end  of  systole,  we  might  represent 
the  normal  and  the  weak  heart,  as  in  the  illustration,  the  dimin- 
ished excursion  of  the  muscle  lowering  the  output. 

Digitalis,  by  increasing  the  tone  and  contractility,  tends  to 


158 


PHARMACOLOGY  AND    THERAPEUTICS 


bring  the  heart  muscle  back  to  normal,  and  so  increases  the  out- 
put. Its  site  of  action  in  producing  this  effect  may  be  deter- 
mined by  administering  a  large  dose  of  atropine  to  a  laboratory 
animal  to  eliminate  vagus  effects,  and  a  dose  of  apocodeine  to 
cut  off  the  accelerators.  All  influences  through  the  nervous 
system  are  thus  removed,  but  digitalis  still  results  in  striking 
increase  in  contractility  and  tonicity.  It  must,  therefore,  stimu- 
late the  muscle  itself.  It  gives  these  effects  with  decided  force 
in  the  laboratory,  and  probably  to  some  extent  in  therapeutics. 

The  right  ventricle,  though  its  muscular  wall  is  normally  much 
thinner,  is  stimulated  as  much  proportionally  as  the  left.  In 
those  cases  in  which  the  right  ventricle,  through  compensation, 
has  become  thick  and  strong,  the  employment  of  digitalis  may 
easily  result  in  harm,  especially  if  the  heart  shows  " normal 
rhythm."     (See  Mitral  Stenosis  below.) 

The  papillary  muscles  are  also  strengthened  and  toned,  a 
matter  of  special  importance  in  a  weak,  dilated  heart.  For 
these  muscles  must  contract  coincidentally  with  the  ventricle,  or 


As 


\  \  \:  w:  \v\ 


Vs 


Fig.  8. — Diagram  to  illustrate  "ventricular  extrasystole."  .4s,  Auricular  sys- 
toles; Vs,  ventricular  systoles.  At  *  the  ventricle  beats  spontaneously.  This 
beat  is  followed  by  a  refractory  period,  during  which  the  regular  auricular  im- 
pulse is  ineffective,  and  the  ventricle  does  not  beat  until  the  next  auricular  im- 
pulse.    The  auricle  beats  regularly  throughout. 

they  will  allow  the  valves  to  bulge  into  the  auricle  during  systole 
and  make  a  relative  insufficiency,  i.  e.,  a  leakage  backward.  As 
a  matter  of  fact,  the  normal  ventricular  contraction  begins  in 
the  papillary  muscles. 

2.  Irritability  or  excitability  is  the  susceptibility  to  stimuli. 
Normally,  it  does  not  determine  the  rate  of  the  heart,  for  the 
normal  pacemaker  is  the  sinus  node.  But  an  increase  of  irri- 
tability beyond  the  normal  tends  to  result  in  spontaneous  mus- 
cular contractions  that  do  not  have  their  origin  in  the  sinus  node. 
The  effects  of  these  are  harmful.  They  may  be  produced  by 
digitalis. 

Overirritability  or  over  excitability  may  show  in  auricular  or 
ventricular  premature  beats,  in  paroxysms  of  tachycardia,  in 
auricular  fibrillation,  or  in  ventricular  fibrillation.  In  some 
excitable  hearts  there  are  alternations  of  premature  beats, 
paroxysmal  tachycardia,  and  auricular  fibrillation. 


DIGITALIS 


159 


(a)  Premature  Beats. — One  of  the  earliest  indications  of  exces- 
sive irritability  is  the  premature  or  interpolated  or  abortive  beat, 
the  so-called  extrasystole,  a  beat  which  has  its  origin  elsewhere 


Fig.  9. — Ventricular  extrasystoles  developing  in  a  heart  with  normal  rhythm  and 
moderate  dilatation.  This  resulted  from  10  minims  (0.7  c.c.)  of  tincture  of  digi- 
talis and  20  minims  (1.3  c.c.)  of  tincture  of  nux  vomica  three  times  a  day.  It 
ceased  within  two  days  of  stopping  the  medicine.  (Top  line,  apex;  lower,  radial  pulse.) 

than  at  the  sinus  node.  The  site  of  origin  may  be  the  auricle, 
the  result  being  a  premature  auricular  beat,  followed  by  a  cor- 
responding premature  ventricular  beat  in  response  to  the 
auricular  stimulus.  But  much 
more  commonly  the  premature 
beat  has  its  origin  in  the  ventri- 
cle, the  ventricle  alone  giving  a 
premature  beat,  while  the  au- 
ricular rhythm  is  not  affected. 
A  premature  beat  may  appear  at 
regular  intervals  or  irregularly, 
and  frequently  or  infrequently. 
It  may  follow  the  normal  beats 
so  that  the  ventricle  beats  in 
couples.  It  may  show  in  the 
radial  pulse  or  it  may  not,  but  it 
is  an  irregularity  of  the  heart 
and  not  an  intermittence.  In 
susceptible  hearts  it  may  some- 
times accompany  or  follow  hold- 
ing the  breath.  It  is  one  of  the 
most  commonly  observed  of  the 
toxic  manifestations  of  digitalis. 

(b)  In  auricular  fibrillation  the  auricular  muscle  is  in  a  state 
of  such  excitability  that  muscle  groups  here  and  there  contract 
independently,  i.  e.,  the  fibers  quiver  or  nbrillate,  instead  of  con- 
tracting coordinately  to  make  an  auricular  beat.     The  ribrilla- 


Fig.  10. — From  same  case  as  Fig.  9. 
Every  fourth  beat  is  premature.  Top 
line  jugular;  middle,  apex;  lower,  radial. 


i6o 


PHARMACOLOGY  AND  THERAPEUTICS 


tions  occur  at  the  rate  of  several  hundred  per  minute,  and  their 
effect  upon  the  ventricle  is  to  make  it  beat  in  a  rapid,  irregular, 
and  disorderly  manner.  In  a  pulse-tracing  of  this  condition 
unmodified  by  drugs — (a)  No  two  sections  are  alike,  the  radial 
pulse  being  irregular  and  disorderly;  (b)  the  height  of  the  pulse 
wave  has  no  definite  relation  to  the  length  of  the  preceding  pause ; 


Fig.  ii. 


Fif 


r>K.     *       ,•    VA     k 


AAMfMAHA* 


T&rc'uta^  Khf    Gf*l3//i,         Rite,  loo 


Fig.  13. — Auricular  fibrillation  and  complete  heart-block  developing  in  a  case 
of  cirrhosis  of  liver,  with  weak  heart,  but  with  normal  rhythm.  Digipuratum, 
\]/2  grains  three  times  a  day,  was  given  from  April  17th  to  20th,  when 
tracing  showed  auricular  fibrillation  and  complete  heart-block,  rate  42.  The 
drug  was  stopped,  and  two  days  later  tracing  12  showed  auricular  fibrillation 
alone,  rate  about  135.  Tracing  13  taken  the  next  day  showed  return  to  normal 
rhythm,  rate  100.  Similar  phenomena  followed  the  administration  of  digitalis 
a  month  Inter. 


and  (c)  the  jugular  tracing  shows  absence  of  the  normal  auricular 
waves,  and  in  most  instances  numerous  small  fibrillation  waves. 

Auricular  fibrillation  may  exist  without  serious  symptoms, 
but  it  is  usually  serious,  is  one  of  the  most  frequent  causes  of 
lack  of  compensation,  and  may  be  the  precursor  of  ventricular 
fibrillation  and  death. 


DIGITALIS  l6l 

(c)  In  paroxysmal  tachycardia  the  heart  is  regular  or  nearly 
so,  but  very  rapid,  the  rate  being  usually  over  150.  The  beats 
may  have  their  origin  in  the  auricle,  in  the  ventricle,  or  at  the 
auriculoventricular  node.  If  the  tachycardial  beats  originate 
at  the  auriculoventricular  node,  there  is  true  nodal  rhythm,  and 
the  auricle  and  ventricle  receive  their  stimulus  at  the  same  time, 
and  consequently  beat  simultaneously.  If  the  tachycardial 
beats  originate  in  the  ventricle,  there  may  be  a  reversed  or  retro- 
grade rhythm,  the  excitable  ventricle  beating  prematurely  and 
imposing  its  rhythm  upon  an  auricle  in  a  similar  state  of  excit- 
ability. The  ventricle  may  pass  into  a  state  of  fibrillation, 
which  almost  invariably  means  immediate  death. 

(d)  Ventricular  fibrillation  is  the  usual  terminal  effect  of 
digitalis    poisoning    in    mammal    experiments     (Cushny).     It 


Fig.  14. — Extrasystoles  and  paroxysmal  tachycardia.  Case  with  auricular 
fibrillation.  Digitalis,  \l/2  grains  for  four  days,  resulted  in  alternating  periods  of 
halving  of  the  pulse-rate  due  to  extrasystoles,  and  very  rapid,  almost  regular 
pulse  (paroxysmal  tachycardia). 


corresponds  in  mammals  with  the  continuous  systole  in  cold- 
blooded animals.  It  seems  to  be  the  usual  finding,  but  Eckler 
(191 2)  reports  that  after  death  from  digitalis,  strophanthus,  and 
ouabain,  12  out  of  62  mammal  hearts  were  found  in  systolic 
contraction. 

C.  The  Auriculoventricular  Bundle. — The  function  of  this 
bundle  is  to  conduct  impulses  from  the  auricle  to  the  ventricle, 
so  that  normally  the  ventricular  beat  follows  that  of  the  auricle 
in  practically  one-fifth  of  a  second.  The  effect  of  digitalis  on 
this  bundle  may  be  the  retardation  or  prevention  of  conduction. 
This  is  usually  a  result  of  vagus  stimulation,  and  it  may  be  pre- 
vented by  atropine.  But  in  some  cases,  as  demonstrated  by 
Cushny,  the  effect  of  digitalis  on  conduction  is  not  prevented  by 
atropine,  and  in  these  digitalis  presumably  has  a  direct  action 
upon    the    junctional    tissues,    either    the    auriculoventricular 


162 


PHARMACOLOGY  AND  THERAPEUTICS 


bundle  proper,  or  the  junctions  of  its  ramifications  with  the 
proper  muscles  of  the  ventricles. 

In  therapeutics,  a  prolongation  of  the  auriculoventricular 
interval,  e.  g.,  to  three-tenths  or  three-fifths  of  a  second  (incipient 
heart-block),  is  not  uncommon  from  digitalis.  It  is  an  effect  that 
can  be  ascertained  only  by  tracings,  but  it  is  a  toxic  manifesta- 


Fig.  is- 


'lA/kX^>    Sl/WCC  sJw-a<    lb"— 


\  <^_ 


jui!\AAJ\MM!\J 


l*/vt\Aw  -*A-wiUi  t^  TJ  V<£/tft\j-y 


Fig.  1 6. 

Figs.  15  and  16. — Complete  heart-block.  Developing  after  digipuratum,  i}4 
grains  three  times  a  day  for  nine  days.  Fig.  16  shows  return  to  normal  rhythm 
after  the  digitalis  effect  had  worn  off.  This  block  was  suspected  when  a  pulse  that 
had  been  beating  between  106  and  116  for  several  days  suddenly  changed  to  a  rate 
between  60  and  70. 


tion  and  calls  for  stoppage  of  the  drug.  More  rarely  seen  from 
digitalis,  but  much  more  serious,  is  a  degree  of  interference  with 
conduction  which  results  in  occasional  or  frequent  failure  of  the 
ventricle  to  beat  in  response  to  the  auricle,  i.  e.,  a  state  of  partial 
heart-block.  In  this  the  auricle  beats  faster  than  the  ventricle. 
In    mild    degrees    the    auriculoventricular    interval    gradually 


DIGITALIS 


163 


lengthens,  or  suddenly  lengthens,  so  that  the  ventricle  intermits 
at  regular  intervals,  i.  e.,  skips  every  tenth,  seventh,  third,  etc., 
beat,  the  tracings  showing  an  independent  auricular  beat  during 
the  ventricular  intermission;  and  the  stethoscope  no  ventricular 
contraction.  In  marked  stages  the  ventricle  beats  only  in 
response  to  every  second  or  third  auricular  beat,  i.  e.,  in  2  :  1  or 


1 

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16 

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52 

Fig.  17. — Chart  comparing  the  effect  of  digitalis  in  cases  having  auricular  fib- 
rillation with  those  having  a  normal  rhythm.  The  black  dots  represent  the  rate 
with  auricular  fibrillation  and  the  white  with  the  normal  rhythm.  The  side  fig- 
ures represent  pulse-beats.  The  top  figures  represent  days  (James  Mackenzie 
in  "Heart,"  vol.  ii,  No.  4,  191 1). 


3  :  1  rhythm,  the  pulse  being  slow  and  regular.     In  these  last 
states  fainting  spells  are  not  uncommon. 

Still  less  frequent  from  digitalis  is  complete  heart-block,  in 
which  the  ventricle  receives  no  adequate  stimulus  from  the  auricle, 
and  consequently  beats  at  its  own  intrinsic  rate,  with  entire 
disregard  of  the  auricular  beat.  In  the  complete  block  of  dis- 
ease the  rate  of  the  ventricle  is  in  the  neighborhood  of  30,  and 
this  is  the  normal  intrinsic  rate  of  the  human  ventricle.     But  in 


164  PHARMACOLOGY  AND  THERAPEUTICS 

the  complete  block  from  digitalis,  owing  to  the  increase  in  mus- 
cular irritability,  the  rate  tends  to  be  faster,  and  may  even  exceed 
that  of  the  auricle  (Hewlett  and  Barringer).  In  this  last  type, 
in  the  absence  of  a  careful  study  of  tracings,  the  block  may 
remain  undetected.  In  ordinary  cases,  however,  bradycardia 
should  suggest  the  possibility  of  block ;  and  in  any  heart  a  block 
should  always  be  suspected  when  there  is  a  sudden  slowing  of  the 
ventricular  rate  with  regularity.  In  auricular  fibrillation  a 
complete  block  is  shown  by  the  striking  change  from  rapidity 
and  irregularity  in  the  action  of  the  ventricle  to  slowing  and 
regularity.  Slowing  from  digitalis  may,  therefore,  be  due  to  heart- 
block,  as  well  as  to  an  effect  upon  the  sinus  node. 

When  a  partial  block  is  already  established  by  disease,  digi- 
talis is  very  prone  to  increase  its  severity  or  to  change  it  to 
complete  block.  A  number  of  deaths  presumably  produced  in 
this  way  have  been  reported  from  the  intravenous  use  of  stro- 
phanthin,  the  digitalis  ally. 

The  following  is  an  interesting  case  of  permanently  complete 
heart-block,  in  which  the  digitalis  had  the  effect  of  bringing  on 
short  spells  of  doubling  of  the  intrinsic  rate  of  the  ventricle  with 
retrograde  rhythm.  It  was  a  case  on  Dr.  Norrie's  service  at  St. 
Luke's  Hospital.  In  one  of  my  tracings  from  this  case  the  ven- 
tricular rate  shows  a  sudden  jump  from  26  to  54,  a  drop  of  the 
auricular  rate  from  62  to  54,  and  a  change  of  the  rhythm  to 
"reversed"  or  retrograde,  i.  e.,  the  auricular  systole  followed 
that  of  the  ventricular,  instead  of  preceding  it,  both  having  the 
same  rate.  At  the  end  of  each  such  paroxysm  there  was  a  long 
pause  of  the  ventricle,  lasting  some  seconds,  during  which  the 
patient  had  a  passing  attack  of  faintness  or  light-headedness, 
though  lying  flat  in  bed. 

Such  a  pause,  sometimes  following  the  doubling  of  a  slow 
ventricular  rate,  is  prone  to  occur  in  partial  or  complete  heart- 
block,  and  may  be  accompanied  by  feelings  of  faintness,  loss  of 
consciousness,  or  an  epileptiform  convulsion,  the  typical  Stokes- 
Adams  attack.  These  effects  are  due  to  a  momentary  anemia 
of  the  medullary  centers,  the  result  of  the  ventricular  stoppage. 
They  are  likely  to  be  more  serious  if  the  patient  is  in  the  upright 
position. 

D.  Combined  Effects. — In  cases  with  auricular  fibrillation 
already  established  from  disease  the  combined  effects  on  irri- 
tability and  conduction  are  strikingly  to  be  observed  after  digi- 
talis. The  therapeutic  effect  of  the  drug  in  auricular  fibrillation 
is  not  to  overcome  the  fibrillation,  so  far  as  we  know,  but  essen- 
tially to  impair  conductivity.  It  thus  checks  the  passage  of  the 
frequent  small  and  irregular  auricular  impulses,  which  in  this 


DIGITALIS 


l65 


condition  serve  only  to  nag  the  ventricle  and  make  its  action 
disorderly.  In  other  words,  it  establishes  a  degree  of  heart-block. 
The  effect  is  partly  due  to  vagus  stimulation,  and  pressure 
on  the  vagus  in  the  neck  will  sometimes  momentarily  produce 
a  similar  result,  while  atropine  will  prevent  it.  It  is  prob- 
ably also,  in  some  instances,  due  to  a  direct  action  of  the  digitalis 
on  the  junctional  tissues  (Cushny).     The  block  may  become 


'^VvkJK'^^'^^^  ^  ** 


F"Tlc/v 


f»t**.iVi  ll\ 


v  V  VW  Y 


Fig.  18. 


Fig.  19. 

Figs.  18  and  iq. — Complete  heart-block  developing  in  a  case  with  auricular 
fibrillation.  On  admission  (tracing  18)  the  ventricle  was  very  irregular,  rate  146  to 
200,  with  a  countable  radial  pulse  of  80  to  94.  Infusion  of  digitalis,  4  drams  thrice 
daily,  was  given  for  eleven  days,  then  stopped.  At  this  time  the  pulse  was  nearly 
regular,  rate  about  72.  Four  days  later  tracing  iq  was  taken,  the  pulse  being  quite 
regular,  rate  54.  Three  days  later,  /'.  e.,  one  week  after  the  stoppage  of  the  drug, 
the  complete  block  was  still  present,  the  ventricular  rate  remaining  between  50  and 
60. 


complete,  with  regularity  of  the  ventricular  beats  and  a  slowed 
rate,  and  this  is  an  undesirable  effect. 

But  more  frequently  in  auricular  fibrillation  digitalis  results 
in  a  condition  in  which,  owing  to  the  state  of  excitability  of  the 
muscle,  each  beat  that  occurs  in  response  to  an  auricular  stimulus 
is  followed  quickly  by  another  beat  which  originates  in  the  ven- 
tricle.    Thus  the  beats  appear  in  pairs  or  couples,  and  make 


i66 


PHARMACOLOGY  AND  THERAPEUTICS 


" coupled  rhythm."  In  this  the  distance  between  the  members 
of  a  couple  is  fairly  constant,  while  that  between  the  couples  may 
vary  considerably;  and  the  second  beat  of  the  pair  may  or  may 
not  be  palpable  at  the  wrist.  What  is  probably  an  early  stage 
of  coupled  rhythm  is  an  alternation  of  single  beats  with  coupled 
beats.  A  serious  stage  of  it  is  present  when  the  distance  between 
the  couples  is  short,  so  that  the  ventricle  beats  very  rapidly. 
Coupled  rhythm  is  a  common  digitalis  manifestation  in  auricular 


(IfKXP. 


Fig.  20. — Coupled  rhythm  developing  in  a  case  of  auricular  fibrillation. 
This  is  an  exceedingly  common  effect.  It  resulted  after  five  days  of  powdered 
digitalis,  2  grains  three  times  a  day. 


Ca,s  e  cjj  Ocjk  U,iM«*yi  bt  i/UciA/vow 


VN 


Fig.  21. — Phasic  arhythmia  developing  in  a  case  of  auricular  fibrillation. 
This  followed  digalen,  10  minims  every  four  hours,  for  one  day,  and  digipuratum, 
\yi  grains  three  times  daily  for  two  days. 


fibrillation,  but  is  sometimes  also  present  with  normal  rhythm, 
every  second  beat  being  a  premature  one. 

Another  digitalis  effect  in  auricular  fibrillation  is  "phasic 
arhythmia, "  which  corresponds  in  general  character  with  that 
arising  from  the  sinus,  but,  so  far  as  known,  has  its  origin  not  at 
the  sinus,  but  in  the  ventricle.  Cohn  has  discovered  that  in 
some  cases  vagus  fibers  pass  directly  to  the  ventricle,  and  it  may 


DIGITALIS 


167 


be  that  phasic  arhythmia  occurs  only  in  such  cases  and  is  a  vagus 
effect. 

E.  The  Coronary  Arteries. — (a)  Constriction  of  the  coronary 
arteries  is  a  real  digitalis  effect,  as  shown  by  perfusion  experi- 
ments. In  the  coronaries  of  young  rabbits  a  solution  of  1  :  20,000 
reduced  the  outflow  from  8  c.c.  per  minute  to  3  c.c.  (Dixon). 
From  therapeutic  amounts,  this  action  is  probably  negligible, 
for,  as  Hatcher  suggests,  it  seems  improbable  that  the  improve- 
ments in  the  circulation  from  digitalis  could  occur  if  the  coro- 
naries were  constricted. 

In  acute  poisoning,  however,  coronary  constriction  may  be  a 
factor  in  weakening  the  muscle;  and  in  cumulative  poisoning, 
it  may  be  the  cause  of  the  muscular  weakness  which  manifests 
itself  by  alternating  weaker  and  stronger  beats,  the  condition 
known  as  "pulsus  alternans."  This  seems  probable  because 
the  conditions  in  which  pulsus  alternans  not  due  to  digitalis  is 
observed  are  those  in  which  the  coronary  circulation  is  probably 
inadequate,  viz.,  myocarditis  with  coronary  sclerosis,  the  cardiac 
hypertrophy  of  nephritis,  and  paroxysmal  tachycardia.  In 
coronary  sclerosis  the  coronary  blood-flow  is  retarded.  In 
hypertrophy  a  much  larger  blood-supply  than  usual  is  required, 
and  a  time  may  come  when  the  coronary  flow  cannot  meet  the 
needs  of  the  large  mass  of  muscle.  In  a  rapid  tachycardia  the 
diastolic  pause  is  much  shortened,  and,  as  the  coronary  circula- 
tion goes  on  essentially  during  diastole,  obviously  causes  a 
serious  interference  with  the  cardiac  blood-supply.  Pulsus 
alternans  may,  therefore,  be  a  coronary  effect,  and  when  it 
results  from  digitalis,  is  a  decidedly  toxic  one. 

(b)  Nutrition  and  Recuperative  Power. — The  increased  pres- 
sure in  the  aorta  invigorates  the  coronary  circulation,  and  the 
prolonged  diastasis  from  slowing  allows  it  to  last  longer.  At 
the  same  time  the  greater  contraction  in  systole  promotes  the 
emptying  of  the  coronary  veins.  The  result  is  not  only  a  greater 
supply  of  food  and  oxygen  to  the  heart,  to  nourish  it  and  permit 
of  recuperation,  but  also  a  greater  supply  of  the  drug  to  the 
heart  muscle  to  keep  up  its  stimulation. 

Hare  (1897)  has  shown  how  digitalis  can  improve  the  heart's 
nutrition  in  growing  animals,  and,  as  a  result,  probably  the 
general  nutrition.  Of  a  litter  of  10  pigs  two  months  old,  he  kept 
5  as  a  control,  and  treated  the  other  5  with  normal  liquid  digi- 
talis. The  dose  was  2  minims  twice  a  day  for  a  month.  It  was 
then  gradually  increased  until,  at  the  end  of  three  months,  it  was 
10  minims  twice  a  day.  The  food  was  the  same  for  all.  There 
were  no  poisonous  manifestations.  After  four  and  a  half  months 
the  digitalis  pigs  averaged  4  pounds  heavier  than  the  others,  and 


1 68  PHARMACOLOGY  AND    THERAPEUTICS 

their  hearts  averaged  heavier  by  more  than  \  ounce.  On 
examination  by  W.  M.  L.  Coplin  the  ventricular  walls  were 
thicker,  firmer,  and  more  resistant  on  cutting,  and  their  mus- 
cular fibers  measured  0.02  mm.  wider  (average),  i.  e.,  TV  to  A 
larger  than  those  of  the  control  pigs. 

Cloetta  (1905)  gave  digitalis  for  several  months  to  adult 
normal  rabbits,  without  effect  upon  the  size  of  the  heart.  Then 
he  artificially  produced  aortic  regurgitation,  keeping  some  of  the 
rabbits  as  controls,  while  to  others  he  gave  digitalis.  The 
hearts  of  the  treated  animals  were  much  more  hypertrophied  and 
more  dilated  than  those  of  the  controls,  and  were  capable  of 
much  greater  stimulation.  Their  aortas  were  also  less  dilated 
than  those  of  the  controls.  These  experiments  would  go  to 
show  that  in  growing  animals  and  in  hearts  that  required  com- 
pensatory hypertrophy  digitalis  might  improve  the  coronary 
circulation  and  the  nutrition  of  the  heart. 

Summary. — Digitalis  may  affect  the  heart  in  regard  to  its 
rate  and  rhythm;  its  tonicity,  contractility,  irritability,  and 
conductivity;  its  nutrition,  oxygenation,  and  recuperation. 
Through  its  action  on  the  vagus  it  may  produce  loss  of  tonicity, 
slowing,  phasic  arhythmia,  momentary  standstill,  or  blocking  of 
the  auricular  impulses  in  their  passage  to  the  ventricle.  Through 
its  action  on  muscle  it  may  increase  the  tonicity,  the  con- 
tractility, and  the  irritability,  the  last  to  a  dangerous  degree. 

F.  The  Systemic  Arteries. — Besides  its  effect  upon  the  struc- 
tures of  the  heart,  digitalis  in  the  laboratory  may  produce  another 
effect  on  the  circulatory  organs,  viz.,  contraction  of  the  peripheral 
arteries.  The  evidence  of  this  is:  If  a  loop  of  dog's  intestine 
in  situ  is  inclosed  in  an  oncometer  so  that  any  change  in  its  volume 
can  be  measured,  the  administration  of  a  laboratory  dose  of 
digitalis  is  seen  to  be  followed  by  shrinkage  in  the  volume  of  the 
intestine.  The  shrinkage  is  synchronous  with  a  heightened 
general  arterial  pressure,  and  is  due  to  contraction  of  the  vessels. 
If  the  splanchnic  nerves  are  cut  so  as  to  remove  connection  with 
the  centers,  the  shrinkage  is  less  than  before,  therefore  stimula- 
tion of  the  vasoconstrictor  center  is  an  effect  of  the  drug. 

Further,  in  perfusion  of  an  isolated  loop  of  intestine  or  of  a 
severed  leg,  i.  e.,  of  organs  removed  from  connection  with  the 
nerve-centers,  if  digitalis  is  added  to  the  perfusing  fluid,  the 
venous  outflow  is  decreased.  This  effect  is  due  to  J:he  contrac- 
tion of  the  arterioles,  and  shows  that  there  is  a  peripheral  vaso- 
constrictor effect.  The  peripheral  effect  may  be  analyzed— 
(a)  by  the  use  of  apocodeine  or  ergotoxin,  two  drugs  which 
paralyze  vasoconstrictor  nerve-endings;  the  digitalis  still  causes 
contraction,  so  must  directly  stimulate  the  arterial  muscle;   and 


DIGITALIS  169 

(b)  by  perfusion  of  a  coronary  or  pulmonary  artery;  these  con- 
tract under  digitalis,  though  they  have  no  vasoconstrictor  nerves. 
There  is  a  slight  stimulation  of  the  vasoconstrictor  nerve-endings, 
but  the  main  peripheral  effect  of  digitalis  is  exerted  on  the  arterial 
muscle.  Thus  digitalis  causes  contraction  of  the  arteries  by  stimu- 
lating the  arterial  muscle  and  the  vasoconstrictor  center,  and  slightly 
by  stimulating  the  vasoconstrictor  nerve-endings. 

The  contraction  of  the  arteries  occurs  mainly  in  the  splanch- 
nic area,  but  ordinarily  occurs  also  in  the  vessels  of  the  limbs. 
After  powerful  doses  the  arteries  of  the  limbs,  as  shown  by  the 
plethysmograph,  may  be  dilated;  for  they  have  less  power  of 
contraction  than  the  splanchnics  and  may  be  forced  into  dilata- 
tion when  the  blood  is  prevented  from  entering  the  splanchnic 
area  (for  it  must  go  somewhere).  The  increased  peripheral 
resistance  in  itself  is  a  resistance  stimulus  to  the  heart,  and,  in 
addition,  promotes  the  coronary  circulation  during  the  diastolic 
pause. 

These  are  the  effects  from  laboratory  doses,  i.  c.,  poisonous 
amounts  administered  intravenously,  and  they  show  the  ten- 
dency of  the  drug.  But  in  practical  therapeutics  the  effect  is  not 
so  striking.  In  fact,  it  is  the  consensus  of  opinion  among  students 
of  the  circulation  that  in  medicinal  doses  digitalis  does  not  cause 
constriction  of  the  arteries  in  measurable  degree. 

Arterial  Pressure. — In  laboratory  animals  digitalis  results  in 
increased  output  of  blood  from  the  heart,  increased  peripheral 
resistance,  and  an  increased  quantity  of  blood  in  the  arteries  at 
the  expense  of  that  in  the  veins.  Hence  we  have  a  decided  rise 
in  arterial  pressure. 

In  man  the  smallness  of  the  dose  and  the  slowness  of  the  drug 
action  permit  the  sensitive  blood-pressure  control  mechanisms 
to  adjust  themselves;  hence  digitalis  in  therapeutic  amounts  may 
cause  no  rise  in  arterial  pressure.  As  Mackenzie  expresses  it, 
"  contrary  to  expectation  the  blood-pressure  is  raised  only  in 
exceptional  cases,  even  when  the  drug  is  repeatedly  pushed  until 
full  physiologic  action  is  apparent,  and  even  when  the  patient  is 
evidently  much  benefited  by  the  drug." 

In  our  own  experience,  a  certain  number  of  heart  cases  have 
shown  decided  improvement  in  arterial  pressure  while  taking 
digitalis;  indeed,  in  a  few  cases  there  has  been  a  very  close  rela- 
tion between  the  amount  of  the  drug  being  taken  and  the  systolic 
pressure.  But  many  other  cases  have  shown  no  effect  at  all 
upon  the  pressure,  though  the  appearance  of  poisonous  symp- 
toms demonstrated  that  full  dosage  was  being  given. 

We  have,  therefore,  reached  the  same  conclusion  as  a  number 
of  other  students  of  the  circulation,  viz.,  that   frequently  the 


170  PHARMACOLOGY  AND   THERAPEUTICS 

improvement  in  the  circulation  under  digitalis  cannot  be  fully 
judged  by  estimations  of  the  arterial  pressure. 

The  Pulmonary  Arteries. — These  tend  to  be  contracted, 
though  the  extent  or  the  significance  of  this  effect  is  not  known. 

The  Cutaneous  Arteries. — The  arteries  of  the  face  and  neck 
tend  to  dilate  and  cause  flushing.  This  seems  to  have  no  appre- 
ciable effect  on  the  general  arterial  pressure,  and  is  not  of  impor- 
tance. It  is  presumably  from  a  central  rather  than  a  peripheral 
action. 

The  Veins.— The  effect  of  digitalis  upon  the  walls  of  the  veins 
is  similar  to  that  upon  the  arteries,  though  it  is  probably  of  no 
therapeutic  significance. 

Kidneys. — The  cardiac  effects  of  digitalis  extend  further  and 
may  be  seen  in  the  action  of  the  kidneys.  With  an  unobstructed 
ureter  a  normal  kidney  will  secrete  more  urine  if  more  blood 
flows  through  it.  And  the  factors  which  affect  the  amount  of 
blood  flowing  through  the  kidney  are:  the  general  arterial  pres- 
sure, the  degree  of  contraction  of  the  kidney  arteries,  and  the 
freedom  of  the  venous  outflow.  Venous  back  pressure,  however 
slight,  or  contraction  of  the  kidney  arterioles,  or  a  fall  in  general 
arterial  pressure,  will  have  a  tendency  to  lessen  the  amount  of 
urine;  while  a  reversal  of  these  conditions  favors  an  increase  in 
the  amount  of  urine. 

As  measured  by  the  oncometer,  the  normal  kidney  of  an 
animal  shrinks  after  a  laboratory  (poisonous)  dose  of  digitalis. 
This  diminution  in  size  is  synchronous  with  the  vasoconstriction 
in  other  parts  of  the  body  and  with  the  rise  in  arterial  pressure, 
hence  it  may  be  assumed  that  the  kidney  arterioles,  in  the  same 
way  as  the  other  arterioles,  are  constricted  by  poisonous  amounts 
of  digitalis.  But  in  human  therapeutics,  as  we  have  seen,  there 
are  presumably  no  essential  constriction  of  arteries  and  no  striking 
rise  in  arterial  pressure.  It  is  a  fact  also  that  the  digitalis  prin- 
ciples apparently  reach  the  kidney  in  such  diluted  form  that,  in 
therapeutic  amounts,  they  have  no  direct  irritant  action  upon  the 
kidney  structures.  Therefore,  the  output  of  urine  in  persons 
with  normal  circulation  is  unaffected. 

Hedinger  (1910)  gave  digipuratum  and  digalen  to  rabbits 
intravenously,  and  when  the  kidneys  were  normal,  obtained  a 
slight  increase  in  the  volume  of  the  kidney,  but  a  scarcely  per- 
ceptible diuresis.  In  the  early  stages  of  tubular  nephritis  he 
obtained  increase  in  kidney  volume  (dilatation  of  the  arterioles) 
and  a  greater  diuresis.  In  more  severe  tubular  nephritis  and  in 
vascular  nephritis  there  was  no  diuresis.  Jonnescu  and  Loewi 
obtained  a  small  diuretic  effect  from  digitalis  in  normal  animals. 


DIGITALIS  171 

They  believed  that  the  drug  could  cause  a  local  dilatation  of  the 
kidney  arterioles,  as  do  most  diuretics. 

In  man,  the  local  action,  if  any,  is  a  negligible  one,  and  not  at 
all  to  be  compared  with  that  of  theobromine.  The  maximum 
increase  in  the  daily  urination  in  health  as  noted  after  digitalis  is 
about  200  c.c,  and  usually  there  is  no  essential  change. 

But  in  cases  with  low  general  arterial  pressure  and  venous 
engorgement,  i.  e.,  in  persons  with  failing  circulation,  there  is 
regularly  very  little  urine  formed ;  and  in  these  cases  the  adminis- 
stration  of  digitalis  may  be  followed  by  a  great  increase  of  the 
kidney  excretion.  In  response  to  digitalis,  in  cases  with  failure 
of  the  circulation  we  have  seen  a  urine  output  of  1 5  or  20  ounces 
a  day  change  to  one  of  100  or  200  ounces,  at  least  for  two  or  three 
days.  So  digitalis  is  diuretic  only  when  it  brings  about  improve- 
ment in  a  poor  circulation. 

Digitalis  diuresis  is  dependent  upon — (a)  improvement  in  the 
general  circulation,  through  which  accumulated  tissue  fluid  passes 
into  the  blood  to  make  hydremic  plethora,  and  (b)  improvement 
in  the  kidney  circulation.  It  is  not  due  to  a  direct  action  of 
the  drug  upon  the  kidney  cells.  Consequently  the  marked 
diuresis  lasts  only  until  the  excess  of  fluid  in  the  body  brought 
about  by  venous  stagnation  is  removed. 

The  urine  is  very  dilute  and  poorly  colored  on  account  of  the 
high  proportion  of  water,  but,  at  least  for  the  first  few  days,  con- 
tains an  actual  increase  in  the  total  solids,  and  particularly  in 
the  salts  and  urea.  It  is  probable  that  this  is  due  to  the  washing 
out  of  stored-up  material. 

In  severe  poisoning,  digitalis  may  result  in  the  appearance  of 
albumin  and  blood  in  the  urine.  This  is  due  either  to  a  remote 
local  irritant  action  resulting  in  nephritis,  or  to  excessive  vaso- 
constriction. Either  of  these  may  also  be  a  cause  of  suppression 
of  the  urine.  {Suppression  is  a  term  to  be  distinguished  from 
retention.  It  signifies  failure  of  the  kidneys  to  secrete  urine, 
while  retention  applies  to  the  bladder,  signifying  failure  of  the 
bladder  to  empty  itself.) 

Venous  Engorgement — Edema  and  Dropsy. — In  cases  with 
failing  circulation  there  is  regularly  some  degree  of  venous  en- 
gorgement, i.  e.,  venous  back  pressure.  And  venous  engorge- 
ment means  - 

1.  Increased  general  capillary  transudation.  This  results  in 
increased  formation  of  tissue  fluid. 

2.  Obstruction  to  the  flow  of  lymph;  because  the  lymphatics 
empty  into  the  veins.    This  checks  the  removal  of  tissue  fluid. 

3.  Lessened  capillary  absorption  of  tissue  fluid,  because  of 
sluggish  blood-flow. 


172  PHARMACOLOGY  AND    THERAPEUTICS 

4.  A  lessened  amount  of  urine.  This  results  in  lessened 
excretion  of  water. 

The  effect  of  the  combined  action  of  these  factors  is  accumula- 
tion of  fluid  in  the  tissue-spaces  and  serous  cavities  of  the  body, 
i.  e.,  edema  and  dropsy.  There  is  "water  retention"  in  the  body, 
and  the  patient  becomes  water-logged.  Edema  is  a  condition  in 
which  there  is  an  abnormal  amount  of  fluid  in  the  tissue-spaces. 
Dropsy  implies  edema,  but  especially  refers  to  abnormal  collec- 
tions of  transuded  fluid  in  serous  cavities. 

By  improvement  in  the  circulation  digitalis  removes  the 
venous  engorgement.  As  a  result,  the  general  capillary  transuda- 
tion, i.  e.,  the  formation  of  tissue  fluid,  is  lessened,  while  at  the 
same  time  improved  capillary  absorption  and  a  proper  flow  of 
lymph  remove  the  excess  of  tissue  fluid.  The  result  is  the 
reduction  of  the  amount  of  accumulated  fluid  in  the  tissue- 
spaces  and  serous  cavities.  This  fluid  passes  to  the  blood, 
swells  its  volume,  and  makes  a  condition  of  hydremic  plethora. 
At  the  same  time  the  rapidity  of  the  renal  blood-flow  is  increased, 
and  this,  together  with  the  hydremic  plethora,  results  in 
diuresis.  Thus  the  excess  of  fluid  is  removed  from  the  blood  and 
eliminated  from  the  body.  The  ultimate  result  is  the  disappear- 
ance of  the  dropsy  and  edema,  without  the  loss  to  the  body  of 
its  albuminous  elements. 

So  digitalis  tends  to  overcome  dropsy  and  edema,  not  by 
simple  removal  of  the  accumulated  blood  from  the  veins  into  the 
arteries,  nor  by  directly  stimulating  the  kidneys,  but — (1)  By 
lessening  general  capillary  transudation;  (2)  by  increasing  the 
lymph-flow  and  promoting  capillary  absorption,  and  (3)  by 
increasing  the  excretion  of  urine.  All  these  depend  upon  its 
power  to  activate  the  circulation;  or,  in  other  words,  its  power  to 
lessen  venous  engorgement. 

The  early  stages  of  edema  are  not  always  obvious,  for  a 
human  being  can  store  a  great  amount  of  liquid  beyond  the  nor- 
mal before  edema  begins  to  show.  But  a  greater  or  less  degree 
of  water-logging  or  water-storage  is  a  regular  accompaniment  of 
a  failing  heart,  so  that  even  when  the  edema  is  not  apparent, 
digitalis  may  prove  diuretic. 

Digitalis  is  of  no  value  as  a  diuretic  in  the  removal  of  serous 
exudations  due  to  inflammatory  or  local  causes,  as  in  cirrhosis 
of  the  liver,  peritonitis,  etc.,  unless  these  are  accompanied  by 
circulatory  inefficiency. 

Value  of  Digitalis. — We  might  sum  up  the  theoretically  valu- 
able effects  of  digitalis  in  a  f ailing  circulation  as  follows : 

1.  On  the  heart:  (a)  Slowing,     (b)  Increased  contractility. 


DIGITALIS  173 

(c)  Increased  tonicity,  (d)  Improved  nutrition,  (e)  In  auric- 
ular fibrillation,  slowing  and  steadying  of  the  ventricular 
rhythm. 

2.  On  the  blood — improved  oxidation  from  improved  pulmo- 
nary blood-flow. 

3.  In  venous  accumulation — the  removal  of  edema  and 
dropsy. 

Respiratory  System. — Therapeutic  doses  have  little  direct 
influence  on  respiration,  but  they  may  stimulate  the  respiratory 
center  through  the  improvement  in  the  cerebral  circulation; 
or  may  help  the  lungs  through  removal  of  congestion  or  edema. 
Poisonous  doses  stimulate  the  respiratory  center  so  that  the 
respiration  becomes  strong  and  deep.  With  the  fall  in  arterial 
pressure  in  the  late  stages  of  poisoning  the  respiratory  center 
fails. 

Nervous  System.— The  brain  may  be  affected  through  its 
increased  blood-supply.  There  is  no  direct  action  except  upon 
the  centers  of  the  medulla.  The  chief  constantly  acting  medul- 
lary centers  are  the  vagus,  the  vasoconstrictor,  and  the  respira- 
tory, and  in  this  sequence  these  are  stimulated  by  the  drug.  If 
poisonous  doses  are  administered,  these  centers  are  eventually 
depressed.  Other  centers  sometimes  affected  by  digitalis  are 
the  heat-regulating,  so  that  temperature  in  fever  tends  to  be 
lowered,  the  vomiting,  and  the  convulsive,  which  may  be  the 
cause  of  convulsions  in  the  late  stages  of  poisoning.  The  nerve- 
endings  which  are  stimulated  are  those  of  the  vagus  and  vaso- 
constrictor nerves. 

Elimination.— The  active  principles  are  excreted  partly  by 
the  kidneys  and  partly  by  the  intestines.  Their  excretion  is 
slow,  so  that  continued  administration  of  large  doses  may  give 
rise  to  cumulative  poisoning.  And  the  administration  of  a  full 
intravenous  dose  of  one  of  the  active  principles  of  the  group 
during  or  following  shortly  after  a  course  of  digitalis  by  mouth 
has,  in  a  number  of  instances,  resulted  fatally.  This  last  state- 
ment is  particularly  true  of  strophanthin,  which  has  been  the 
principle  of  choice  for  intravenous  use. 

The  Digitalis  Allies. — Strophanthus  would  seem  to  be  ab- 
sorbed from  the  alimentary  tract  with  less  rapidity  and  more 
uncertainty  than  digitalis  (Hatcher).  It  is  at  least  50  times  as 
poisonous  to  the  heart  muscle  (Haynes,  Edmunds,  Houghton). 

Either  strophanthin  of  the  Pharmacopoeia,  or  ouabain  {crystal- 
line gratus  strophanthin) ,  may  be  dissolved  in  salt  solution  and 
given  by  deep  intramuscular  injection  or  intravenously.  When 
eV  grain  (1  mg.),  the  maximum  dose,  is  passed  into  a  vein  of  a 
human  being,  it  may  show  its  results  in  slowing  of  the  pulse  in 


174  PHARMACOLOGY  AND  THERAPEUTICS 

from  one-half  to  one  hour,  with  strengthening  of  the  heart. 
This  treatment  may  be  employed  when  the  symptoms  of  the 
cardiac  weakness  are  very  severe,  and  particularly  if  there  is 
auricular  fibrillation. 

Strophanthin  is  said  to  be  eliminated  much  more  rapidly  by 
the  kidneys  than  the  digitalis  glucosides,  so  that  cumulative 
poisoning  does  not  occur.  To  test  this  Frankel  gave  submaximal 
doses  to  a  cat  for  ninety-two  days  and  got  no  symptoms  of  over- 
dosage; Hatcher's  work  corroborates  this.  In  poisoning,  there 
is  no  striking  constriction  of  the  systemic  arteries;  and  Dixon 
has  shown  by  a  perfusion  experiment  that  while  one  part  of  the 
tincture  of  digitalis  in  2500  was  sufficient  to  constrict  strongly 
the  coronary  arteries  of  a  rabbit,  a  similar  strength  of  the  tincture 
of  strophanthus  had  no  effect.  In  a  number  of  cases  the  ap- 
pearance of  diarrhea  is  a  bar  to  the  use  of  strophanthus,  and 
this  is  attributed  to  a  direct  action  of  strophanthin  on  the 
intestinal  muscles. 

Two  things  in  the  action  of  strophanthus  must  be  especially 
noted,  first,  its  smaller  power  to  relieve  conditions  due  to  failure 
of  compensation,  except  when  used  intravenously;  and,  second, 
its  great  toxicity  to  the  muscle  of  the  heart. 

Convallaria  has  no  advantages  over  digitalis  and  is  more  toxic. 

Helleborein,  dose,  ]/2  grain  (0.03  gm.),  has  been  found  ex- 
perimentally to  have  muscular  effects  similar  to  those  of  digi- 
talis, but  without  its  vagus  effects.  Its  application  in  thera- 
peutics has  not  been  determined. 

Toxicology. — 1.  Poisoning  from  an  overwhelming  dose,  as  of 
1  mg.  of  strophanthin  per  kilo  intravenously  in  a  dog,  produces  a 
regular  sequence  of  effects  in  four  well-defined  stages,  with  death 
in  a  few  minutes.  (See  Plate  I.)  The  stages  are:  (1)  Vagus 
and  vasoconstrictor  stimulation,  with  slowed  heart  and  rapid  rise 
in  blood-pressure;  the  diastolic  relaxation  indicating  diminished 
tone.  (2)  Vagus  action  predominating  with  greater  loss  of  tone 
and  heart-block,  or  short  periods  of  vagus  standstill,  and  some- 
times premature  beats  from  muscular  stimulation.  (3)  Muscular 
action  predominating,  with  abrupt  change  to  tachycardia,  the  ven- 
tricle beating  at  a  very  rapid  rate  and  usually  not  in  unison  with 
the  auricle;  arterial  pressure  very  high.  (4)  Muscular  weakness 
with  excessive  irritability,  auricle  fibrillating;  ventricle  losing 
contractility  passes  into  fibrillation  and  death  takes  place.  The 
heart  is  usually  found  in  a  state  of  relaxation,  but  Eckler  (191 2) 
reports  that  as  many  as  1 2  out  of  62  mammal  hearts  were  found  in 
systolic  contraction  after  deaths  from  ouabain,  strophanthus,  and 
digitalis.  Hatcher  has  had  death  occur  in  cats  during  the  intra- 
venous administration;  and  in  a  patient  in  one  of  the  New  York 


DIGITALIS 


175 


hospitals,  death  occurred  three  minutes  after  an  intravenous 
dose. 

2.  Poisoning  From  a  Single  Large  Dose  Taken  by  Mouth. — 
This  is  a  very  rare  event.  Any  one  of  the  actions  upon  the  heart, 
as  outlined  above,  may  manifest  itself.  Excessive  vagus  action 
may  show  in  pronounced  slowing,  sinus  arhythmia,  periods  of 
momentary  cardiac  standstill,  or  some  degree  of  heart-block. 
Excessive  irritability  may  show  in  premature  beats,  auricular 


Fig.  22. — Digitalis  poisoning  in  dog,  showing  intermittent  heart-block.     Upper 
tracing,  auricle;  lower,  ventricle.     The  down-stroke  is  systole. 


fibrillation,  or  paroxysmal  tachycardia.  In  addition,  there  may 
be  nausea,  vomiting,  and  diarrhea;  discomfort  about  the  heart, 
coming  on  early;  deep,  slow  respiration,  or,  in  late  stages,  dysp- 
nea; general  muscular  weakness  with  prostration.  At  a  late 
stage  the  urine  may  be  albuminous  or  bloody,  or  may  be  sup- 
pressed, and  there  may  be  convulsions  which  are  due  either  to 
the  asphyxia  or  to  stimulation  of  the  convulsive  centers.  Death 
takes  place  with  failure  of  the  respiration,  following  collapse. 


176  PHARMACOLOGY  AND  THERAPEUTICS 

But  the  death  occurs  in  spite  of  artificial  respiration,  and  is  due 
to  failure  of  the  circulation  from  ventricular  fibrillation,  which 
in  mammals  usually  takes  the  place  of  the  continued  systole 
of  cold-blooded  animals. 

We  have  recently  had  reported  to  us  one  such  death  from  the 
intravenous  administration  of  digitalis  in  a  human  being,  and 
several  following  the  intravenous  use  of  -£g  grain  (1  mg.)  of 
strophanthin,  death  resulting  in  from  three  minutes  to  about 
an  hour.  Serious  symptoms  have  also  been  reported  from  ^ 
grain  of  digitoxin.  These  deaths  have  usually  occurred  in 
patients  who  had  been  taking  digitalis  for  several  days  previously. 

3.  Cumulative  Poisoning. — This  comes  from  the  use  of  the 
drug  in  medicine.  The  signs  of  overdosage  in  the  medicinal 
administration  of  digitalis  should  be  recognized  as  soon  as  pos- 
sible, for  such  poisoning  is  common  in  hospital  and  private  prac- 
tice, and  its  manifestations  are  not  infrequently  misinterpreted 
as  symptoms  of  the  heart  disease.  But  there  are  a  number  of 
cases  in  which  we  may  be  unable  to  say  with  certainty  that  digi- 
talis is  the  cause,  until  we  note  the  disappearance  of  the  mani- 
festation shortly  after  the  digitalis  is  stopped,  and  its  reappear- 
ance under  further  administration  of  the  drug. 

MANIFESTATIONS  OF  OVERDOSAGE  OF  DIGITALIS 

I.  Subjective  Manifestations: 

a.  Loss  of  appetite,  nausea,  vomiting,  diarrhea. 

b.  Oppression  about  heart,  palpitation,   tachycardia,  con- 

sciousness of  premature  or  skipped  beats. 

c.  Headache. 

II.  Objective  Manifestations: 

a.  Effect  on  sinus  node — 

1.  Excessive  slowing. 

c.  ,     .,     •     (  Exaggerated  respiratory. 

2.  Sinus  arhythmia  Wt  •    * 

J  [  Non-respiratory. 

b.  Effect  on  a-v  bundle 


Prolonged  auriculoventricular  in- 
terval (incipient  block). 

Partial  or  complete  block  (with  or 
without  bradycardia). 


c.  Effect  on  muscle- 


1.  Premature  beats  (extrasystoles). 

2.  Paroxysmal  tachycardia. 
Overexcitability  \  3.  Nodal  and  retrograde  rhythms. 

4.  Auricular  fibrillation. 

5.  Ventricular  fibrillation. 


In  auricular  fibrillation 


DIGITALIS  177 

Combined  effects  on  a-v  bundle  and  on  muscle — 

1.  Complete  heart-block, 
but  little  or  no  brady- 
cardia. 

2.  Coupled  rhythm. 

3.  Phasic  arhythmia. 

2.  In  normal  rhythm — complete  block  without  brady- 
cardia (owing  to  increased  excitability). 
e.  Constriction  of  coronary  arteries — a  possible  influence — 

pulsus  alternans. 
These  have  all  been  explained  in  detail  above. 

In  this  connection  the  possibility  of  persistence  of  effect 
must  be  kept  in  mind,  for,  as  ascertained  by  Hatcher  in  cats, 
the  drug  action  may  continue  in  some  cases  for  as  much  as  three 
weeks  or  a  month  after  a  single  intravenous  dose.  I  have  ob- 
served persistence  of  partial  heart-block  for  three  and  one-half 
weeks  after  the  stoppage  of  digitalis,  and  of  complete  block  for 
at  least  one  week.  Cushny  reports  a  case  of  auricular  fibrillation 
in  which,  through  the  influence  of  digitalis,  "inhibition  had 
gained  a  permanent  control  over  the  heart,"  so  that  the  effect 
persisted  indefinitely  after  the  drug  was  stopped,  or  was  per- 
petuated by  an  occasional  dose.  From  my  clinical  experience  I 
should  judge  that  such  an  effect  in  auricular  fibrillation  is  not 
uncommon. 

Except  when  it  is  administered  intravenously,  the  margin  of 
safety  with  digitalis  is  a  large  one ,  so  that  there  is  no  undue  danger 
in  the  use  of  even  large  doses  by  mouth  or  hypodermatically,  if 
the  administration  is  stopped  when  one  of  the  following  condi- 
tions arises,  viz. : 

1.  Nausea  becomes  marked. 

2.  The  radial  pulse  goes  below  60.     The  pulse  may  become  pro- 

gressively slower  for  a  few  days  after  the  drug  is  stopped, 
hence  the  necessity  for  ceasing  its  administration  before  the 
slowing  has  become  extreme. 

3.  A  rapid  ventricle  with  rate  unaffected  by  digitalis  for  several 

days  suddenly  becomes  slower  (heart-block). 

4.  A  regular  ventricular  rhythm  changes  to  irregular,  as  from  pre- 

mature beats  or  the  development  of  auricular  fibrillation;  or 
becomes  intermittent,  as  from  partial  heart-block. 

5.  Paroxysmal  tachycardia  occurs. 

6.  The  absolutely  irregular  rhythm  of  auricular  fibrillation  becomes 

slow  and  regular  (complete  heart-block),  or  shows  coupled 
rhythm  or  phasic  arhythmia. 
A  considerable  risk  may  be  avoided  by  refraining  from  the  use 


178  PHARMACOLOGY  AND  THERAPEUTICS 

of  digitalis — (a)  When  the  ventricle  is  intermitting;  (b)  when 
there  are  premature  beats;  or  (c)  when  there  is  bradycardia. 

Clinical  reports  of  fatalities  have  borne  out  Hatcher's  findings 
that  an  intravenous  dose  of  any  one  of  the  principles  of  the  group 
is  much  more  active  if  digitalis  has  previously  been  administered 
by  mouth  or  hypodermatically.  For,  as  Hatcher  reports,  even 
as  late  as  a  month  after  the  intravenous  injection  in  a  cat  of  a 
nearly  fatal  dose  of  digitalis,  the  test  animal  may  require  a- 
smaller  intravenous  dose  for  lethal  effect  than  an  animal  that 
has  had  no  digitalis. 

Treatment. — In  the  simplest  condition  of  poisoning,  when 
excessive  slowing  or  irregularity  or  intermittence  of  the  heart,  or 
tachycardia,  begins  to  show,  the  treatment  is  simply  to  stop  the 
drug  and  keep  the  patient  quiet  in  bed  until  the  effect  of  the  drug 
has  worn  off.  To  check  excessive  vagus  action,  atropine  sul- 
phate, -gV  grain  (0.001  gm.),  may  be  employed  hypodermati- 
cally, but  its  effect  lasts  not  over  an  hour.  For  excessive  irri- 
tability, sodium  bromide,  1  to  2  drams  (4-8  gm.),  morphine 
sulphate,  y^  grain  (0.015  gm.),  and  a  hot- water  bag  or  ice-bag 
over  the  heart  may  give  some  relief.  In  severe  poisoning  there 
must  be  absolute  repose  and  freedom  from  exertion  for  several 
days,  the  mere  effort  of  sitting  up  in  bed  being  sufficient  in  some 
cases  to  precipitate  failure  of  the  circulation  and  death.  If 
necessary,  body  warmth  must  be  maintained  by  blankets,  hot- 
water  bottles,  etc.  Symptoms  are  treated  as  they  arise,  there 
being  no  specific  treatment. 

So  far  as  conduction  is  concerned,  there  is  some  evidence  that 
caffeine  tends  to  antagonize  digitalis,  hence  it  may  prove  a  good 
drug  in  heart-block.  On  two  occasions  I  have  seen  caffeine 
apparently  undo  the  work  of  digitalis  in  auricular  fibrillation. 

Therapeutics. — From  our  studies,  it  is  evident  that  the  only 
use  for  digitalis  in  therapeutics  is  to  modify  the  action  of  the 
heart.  And  it  is  to  be  employed  neither  to  constrict  the  arteries 
nor  to  act  directly  upon  the  kidneys.  It  is  also  evident  that 
among  the  cardiac  disturbances  which  require  treatment  there 
are  those  in  which  digitalis  has  a  great  value,  those  in  which  it 
has  a  small  value,  those  in  which  it  has  no  value  at  all,  and  those 
in  which  it  is  distinctly  harmful  or  even  dangerous.  Discrimina- 
tion, therefore,  is  most  essential  in  the  use  of  this  powerful  remedy. 

We  learn  further  that  the  determining  factor  in  our  choice 
of  digitalis  as  the  drug  to  use  is  not  the  state  of  the  valves,  but 
rather  the  functional  condition  of  the  various  parts  of  the  cardiac 
mechanism.  According  to  Lewis,  the  relative  frequency  of 
disorders  of  the  cardiac  mechanism  in  hospital  cases  would  ap- 
proximate as  follows:  Heart-block,  5  per  cent.;  sinus  arhythmia, 


DIGITALIS 


179 


5  per  cent.;  pulsus  alternans,  5  per  cent.;  paroxysmal  tachy- 
cardia, 10  per  cent.;  premature  contractions,  34  per  cent.;  auric- 
ular fibrillation,  4r  per  cent.  The  role  of  digitalis  in  these 
several  conditions  is  as  follows: 

Heart-block. — In  incipient  or  partial  heart-block  digitalis  is 
contraindicated,  for  it  tends  to  increase  the  degree  of  block.  In 
complete  block  it  has  been  recommended  by  Bachmann  and 
others  on  the  ground  that  it  tends  to  bring  the  auricular  and 
ventricular  rates  more  nearly  together,  by  slowing  the  rate  of 
the  auricle  and  increasing  that  of  the  ventricle;  but  in  the  only 
one  of  my  cases  in  which  it  had  any  effect  (see  case  report  under 
Auriculoventricular  Bundle  above)  it  brought  the  auricle 
and  ventricle  to  the  same  rate,  but  in  "reversed  rhythm,'' 
the  auricle  following  the  ventricle  instead  of  preceding  it ;  and 
this  was  harmful. 

Sinus  Arhythmia. — In  this  condition  digitalis  is  useless  and 
probably  harmful.  These  hearts  do  best  when  treated  by  other 
measures  than  drugs. 

Pulsus  Alternans. — In  this  weakened  state  digitalis  may  at 
times  be  of  some  value,  but  its  effects  are  problematic,  and  at 
least  in  some  cases  are  harmful.  Especially  is  this  true  of  the 
myocarditis  cases  with  coronary  sclerosis. 

Paroxysmal  Tachycardia. — As  this  is  a  peculiar  action  of  the 
heart,  coming  on  with  great  suddenness  and  ceasing  just  as 
abruptly,  and  lasting  from  a  fraction  of  a  minute  even  to  months, 
it  is  difficult  to  say  whether  any  drug  given  is  effective  or  not. 
Some  cases  cease  soon  after  the  commencement  of  digitalis  and 
some  do  not.  Where  the  beats  arise  at  the  sinus  node  or  in  the 
auricle,  digitalis  might  be  expected  to  be  of  value  by  retarding 
conduction,  but  when  the  beats  arise  in  the  ventricle,  it  can  only 
be  harmful. 

Premature  Contractions. — Though  a  few  cases  have  been 
reported  of  the  disappearance  of  premature  contractions  during 
the  administration  of  digitalis,  it  is  certain  that  in  most  cases 
digitalis  has  a  decided  tendency  to  increase  these  indications  of 
irritability. 

Auricular  Fibrillation. — Lewis  says  that  "in  hospital  practice, 
of  those  with  obvious  cardiac  failure  at  least  60  per  cent,  have 
auricular  fibrillation."  And  it  is  in  auricular  fibrillation,  above 
all  other  cases,  in  which  there  is  an  almost  ideal  effect  from  digi- 
talis; in  fact,  the  results  of  digitalis  are  dramatic.  Large  doses 
should  be  given  at  the  outset,  and  if  the  fibrillation  is  permanent, 
should  be  followed  by  smaller  doses  once  or  twice  a  week  or  once 
a  day,  for  months,  or  even  throughout  the  life  of  the  patient. 
The  action  of  the  drug  is  not  to  overcome  the  fibrillation,  though 


i8o 


PHARMACOLOGY   AND    THERAPEUTICS 


a  slowing  in  the  rate  of  fibrillation  has  been  noted  (Cushny); 
but,  so  far  as  we  know,  it  is  to  impair  the  conductivity  of  the 
auriculoventricular  bundle,  i.  e.,  to  establish  a  partial  heart- 
block.  The  result  is  that  impulses  from  the  auricle  get  through 
to  the  ventricle  only  at  longer  intervals,  and,  as  a  consequence, 
the  ventricle  becomes  more  nearly  regular,  is  less  rapid,  and  has 
greatly  increased  power.  The  production  of  complete  block, 
shown  by  the  regularity  of  the  pulse,  should  be  avoided;  if  it 
occurs,  it  is  an  indication  for  immediate  reduction  of  the  dose. 

In  a  case  of  auricular  fibrillation,  if  the  condition  is  imme- 
diately serious,  an  intravenous  injection  of  digipuratum,  i}4 
grains  (o.i  gm.),  or  of  strophanthin,  ywu  ^°TS  gram  (0.0005- 
0.001  gm.),  may  be  employed.  But  usually  it  suffices  to  give 
15-30  minims  (1-2  c.c.)  of  the  tincture  three  or  four  times  a  day, 
or  a  corresponding  amount  of  the  powdered  leaves,  i.  e.,  if/2-5 
grains  (0.1-0.2  gm.),  or  of  the  infusion,  i.  e.,  1^2-3  drams 
(6-12  c.c). 

It  is  to  be  noted  that  frequently  the  infusion  is  given  in 
larger  proportional  dosage  •  than  other  preparations.  Doses 
of  ^2  ounce  (15  c.c.)  are  not  unusual,  and  this  dose  is  made 
from  the  same  amount  of  digitalis  as  36  minims  (2.4  c.c.)  of 
the  tincture.  Yet  such  a  dose  of  the  tincture  is  seldom  em- 
ployed. This  is  perhaps  the  reason  why  some  thoughtlessly 
consider  the  infusion  the  better  preparation. 

The  following  table,  giving  the  effects  of  digitalis  as  recorded 
by  Mackenzie  in  a  case  of  mitral  stenosis  with  auricular  fibrilla- 
tion, is  typical: 


Date 


July  6 
8 

9 
10 
11 
12 
13 
14 
15 
16 

17 

18 

19 

20 


Tinct.  Digitalis, 
U.  S.  P. 


37H  minims 
112M       " 


112J 

75 


Pulse-rate 

106 

no 

73 
70 

72 
72 
60 
68 
57 
63 
59 
70 
60 
70 
73 


Oz.  of  Urine 


37 
4i 
29 
37 
52 
63 
42 
16 
14 
27 
16 

3° 
26 

3° 
57 


Remarks 


Headache 
Headache;  nausea 
Vomited;  headache 
Vomited ;  headache 
Better;  no  vomiting 


Breathing  much  easier 


In  cases  in  which  great  excitability  shows  by  varying  periods 
of  auricular  fibrillation,  paroxysmal  tachycardia,  and  premature 


DIGITALIS  181 

ventricular  beats,  digitalis  is  much  less  certain  than  in  simple 
auricular  fibrillation.  For  only  such  beats  as  have  their  origin 
in  the  auricle,  and  consequently  are  affected  by  depression  of 
conductivity,  will  be  favorably  modified  by  digitalis;  while 
those  arising  in  the  ventricle  itself  may  be  made  worse  by  the 
increase  of  excitability.  I  have  recently  seen  four  of  these  cases. 
In  two,  digitalis  gave  good  results;  in  the  other  two  it  did  no 
apparent  good  or  harm. 

In  auricular  flutter,  a  condition  characterized  by  an  extremely 
rapid  auricular  contraction,  rate  about  300,  usually  with  ven- 
tricle beating  at  the  same  rate  or  half  the  rate,  digitalis  changes 
the  flutter  to  fibrillation,  and  this  seems  to  act  by  submerging 
the  original  fast  rhythm  and  restoring  the  rhythm  to  normal. 
Even  if  it  does  not  do  this,  digitalis  will  be  of  value  by  establish- 
ing some  degree  of  block  (Thomas  Lewis). 

Normal  Rhythm. — In  the  cases  in  which  the  heart  is  beating  in 
normal  rhythm  and  is  regular,  but  rapid  and  weak,  it  is  quite 
customary  to  employ  digitalis  with  the  dual  purpose  of  slowing 
the  heart  and  strengthening  its  beat.  And  it  is  in  these  cases,  in 
which  we  desire  and  might  expect  so  much,  that  we  often  meet 
with  disappointment.  At  times  the  drug  seems  utterly  lacking 
in  power  to  check  the  rate  or  to  add  to  the  strength  of  the  heart, 
even  though,  as  shown  by  the  development  of  toxic  effects,  the 
digitalis  is  given  beyond  the  physiologic  limit.  This  may  be 
due  either  to  an  affection  of  the  muscle  caused  by  failure  of 
nutrition  or  the  toxins  of  the  disease,  or  to  reflexes  of  which  we  do 
not  know  the  nature. 

Use  in  High  Arterial  Pressure. — In  this  condition  the  ques- 
tion may  arise  as  to  the  advisability  of  employing  digitalis.  As 
the  doses  administered  in  therapeutics  do  not  have  a  strong 
tendency  to  raise  arterial  pressure,  high  pressure  is  not  of  itself 
a  contraindication  to  the  employment  of  the  drug.  The  author 
has  seen  a  case  of  auricular  fibrillation  with  an  average  systolic 
pressure  of  about  190  do  well  on  digitalis,  the  heart  becoming 
slow  and  steady  without  increase  in  the  arterial  tension.  He 
has  seen  a  number  of  cases  with  tension  between  200  and  260,  in 
which  the  pressure  fell  during  digitalis  administration. 

Use  as  Determined  by  Rhythm  and  Rate. — The  rhythm  serves 
merely  to  determine  the  functional  condition.  The  most  met 
with  rhythms,  with  their  probable  significance,  as  judged  by 
rate,  are  as  follows: 

1.  Ventricle  regular  in  frequency — 

(a)  Pulse  55  to  140 — normal  rhythm — if  rapid,  try  digitalis 
but  watch  for  toxic  manifestations. 

(b)  Pulse  below  55 — heart-block? — avoid  digitalis. 

(c)  Pulse  above  140 — paroxysmal  tachycardia — try  digitalis. 


182  PHARMACOLOGY  AND   THERAPEUTICS 

(d)  Pulse  alternating  weaker  and  stronger  beats — pulsus 
alternans — try  digitalis. 

2.  Ventricle  showing  regular  waxing  and  waning  of  the  rate 
independently  of  respiration — sinus  arhythmia — avoid  digitalis. 

3.  Ventricle  showing  premature  or  abortive  beats — avoid  digi- 
talis. 

4.  Ventricle  beating  in  couples — avoid  digitalis. 

5.  Ventricle  regularly  intermittent — partial  heart-block — avoid 
digitalis. 

6.  Ventricle  persistently  irregular  and  disorderly — auricular 
fibrillation — use  digitalis  in  large  doses. 

The  Influence  of  Conditions  of  the  Heart  and  Arteries  on 
the  Usefulness  of  the  Drug. — (a)  In  Simple  Muscular  Inability 
Without  Valvular  Lesion. 

Simple  Dilatation. —  In  this  the  muscle  has  lost  its  tone  and 
become  abnormally  relaxed,  and  its  contraction  is  weak;  in  addi- 
tion, there  may  be  a  systolic  leakage  through  the  mitral  valves, 
not  due  to  valvular  disease,  but  to  the  dilatation  of  the  mitral 
orifice  and  the  loss  of  tone  of  the  papillary  muscles.  Digitalis 
tends  to  make  the  systole  stronger  and  more  complete,  and,  by 
restoring  the  tone,  prevents  the  abnormal  diastolic  relaxation 
and  weakness.  At  the  same  time,  the  mitral  ring  contracts  to 
normal  again  and  [the  papillary  muscles  are  toned,  so  that  the 
relative  insufficiency  of  the  mitral  valves  disappears.  The 
result  is  an  efficient  circulation.  In  the  moderate  dilatation  of 
acute  febrile  diseases  digitalis  may  be  ineffective  because  of  the 
toxic  action  of  the  bacterial  products. 

Chronic  Myocarditis  and  Fatty  Degeneration. — In  these  a 
portion  of  the  muscle  substance  is  changed  and  replaced  by  non- 
contractile  tissue  (connective  tissue  in  myocarditis ;  fat  in  fatty 
degeneration),  so  that  the  drug  has  less  muscle  substance  to 
stimulate  by  direct  action.  In  some  of  these  cases,  too,  there  is 
impairment  of  the  coronary  circulation  by  coronary  sclerosis ;  and 
in  some  the  slowing  of  the  heart  takes  place  without  a  correspond- 
ing increase  in  ventricular  strength,  so  that  the  output  is  actu- 
ally lessened  instead  of  increased.  Because  of  these  things, 
therefore,  digitalis  may  be  contraindicated,  or  at  least  must  be 
used  with  caution. 

In  Acute  toxic  myocarditis,  as  in  the  infectious  febrile  dis- 
eases, digitalis  often  fails  either  to  slow  or  to  strengthen  the 
heart.     In  some  cases,  however,  it  is  effective. 

(b)  Muscular  Inability  Associated  with  a  Valvular  Lesion. — 
The  common  valvular  defects  are  those  of  the  left  heart,  and 
they  either  make  a  valve  inefficient  so  as  to  permit  backward 
leakage  or  regurgitation,  or  cause  a  narrowing  or  stenosis  of  the 


DIGITALIS  183 

valvular  orifice  so  as  to  obstruct  the  onward  passage  of  the  blood. 
The  common  valvular  lesions  which  allow  regurgitation  of  blood 
are  mitral  insufficiency  and  aortic  insufficiency.  The  common 
lesions  which  cause  obstruction  to  the  passage  of  blood  are 
mitral  stenosis  and  aortic  stenosis. 

In  mitral  insufficiency  there  is  a  systolic  regurgation  of  blood 
from  the  ventricle  into  the  auricle  through  the  insufficient  mitral 
valve.  This  leakage  is  ordinarily  compensated  for  by  enlarge- 
ment of  the  ventricular  cavity  and  hypertrophy  of  the  heart 
muscle.  When  the  muscle  fails,  there  is  a  condition  of  flabby 
heart-wall  and  papillary  muscles,  with  relaxed  mitral  orifice, 
resembling  that  in  simple  dilatation,  but  with  a  permanent 
mitral  leak.     In  this  condition  digitalis  may  prove  valuable. 

In  aortic  insufficiency  there  is  a  diastolic  regurgitation  from 
the  aorta  through  the  insufficient  aortic  valves  back  into  the 
ventricle.  In  this  condition  the  left  ventricle  is  usually  very 
large  and  its  capacity  enormously  increased.  In  the  arterio- 
sclerotic type  the  aorta  is  impaired,  there  is  usually  more  or  less 
myocarditis  and  general  arteriosclerosis,  and  the  failure  of  the 
sclerosed  coronaries  to  meet  the  needs  of  the  very  large  heart  is 
probable.     Hence  digitalis  should  be  used  with  caution. 

In  the  endocarditic  type  the  dilatation  and  hypertrophy  of  the 
ventricle  through  the  natural  compensatory  changes  are  regularly 
very  marked,  the  heart  is  enormous,  and  there  is  a  very  great 
output  of  blood  at  each  systole.  This  factor  and  the  prompt 
leakage  are  enough  to  make  a  great  difference  between  the  systolic 
and  diastolic  aortic  pressures,  hence  a  sudden  great  distention  of 
the  aorta  in  systole,  a  matter  of  importance  if  there  is  aortic 
disease.  In  such  a  case  the  prolongation  of  diastole  by  digitalis 
does  not  seem  to  make  any  serious  difference  so  far  as  the  leakage 
is  concerned  (Stewart),  and  it  allows  a  longer  time  for  the  addi- 
tional coronary  blood-supply  needed  by  the  greatly  hyper- 
trophied  wall  of  the  heart. 

The  peripheral  pressure,  however,  is  not  influenced  so  much 
by  the  size  of  the  leak  as  by  reflexes  through  the  depressor  nerve, 
which  in  man  runs  afferently  in  the  vagus  from  the  heart  or  from 
the  adjoining  portion  of  the  aorta.  When  the  intra-aortic  pres- 
sure is  abnormally  high,  this  nerve  carries  impulses  which  result 
in  a  reflex  dilatation  of  the  peripheral  arterioles.  So  in  aortic 
insufficiency,  either  because  of  the  very  high  aortic  systolic 
pressure  or  the  sudden  overdilatation  of  the  aorta  from  the  great 
output  at  a  single  beat,  depressor  impulses  are  set  going;  and 
there  is  immediately  a  reflex  dilatation  of  the  arterioles,  which 
causes  greatly  lessened  peripheral  resistance  and  low  diastolic 
pressure.     Whether  or  not  digitalis,  through  its  effect  upon  the 


184  PHARMACOLOGY  AND   THERAPEUTICS 

vasoconstrictor  mechanism,  may  counteract  this  depressor 
reflex,  which  is  protective  by  letting  off  at  the  periphery  the  exces- 
sive pressure  caused  by  the  great  output  in  systole,  is  a  question. 
If  it  does  so,  it  may  be  harmful. 

In  mitral  stenosis  the  mitral  orifice  is  narrowed  by  thickening 
of  the  valves  or  their  adherence  together  so  as  to  obstruct  the 
rilling  of  the  ventricle  from  the  auricle.  The  natural  compensa- 
tion in  this  case  is  secured  through  hypertrophy  and  dilatation 
of  the  left  auricle  and  of  the  right  ventricle,  so  that,  by  added 
pressure,  the  proper  amount  of  blood  is  forced  through  the  nar- 
rowed aperture.  Under  digitalis,  on  the  one  hand,  the  filling  of 
the  left  ventricle  through  this  narrowed  orifice  is  favored  by  a 
lengthened  diastole  (and  the  strengthening  of  the  left  auricle  and 
right  ventricle),  and  this  has  a  slight  tendency  to  improve  the 
systemic  circulation.  On  the  other  hand,  digitalis  does  not  re- 
move the  stenosis;  and  there  is  always  the  possibility  that  while 
the  obstruction  to  the  exit  of  blood  at  the  mitral  orifice  remains 
unchanged,  any  increased  output  from  a  right  ventricle  already 
dilated  and  hypertrophied  may  result  merely  in  increased  pul- 
monary engorgement.  This  shows  in  congestion  at  the  bases  of 
the  lungs,  transudation  of  fluid  into  the  pleural  cavity,  edema 
of  the  lungs,  or  hemorrhage  from  the  lungs. 

So  in  mitral  stenosis,  when  the  auricle  and  ventricle  are 
beating  in  normal  rhythm,  the  systemic  circulation  gets  but  little 
help  from  digitalis,  and  the  danger  of  congestion  in  the  lungs  is 
increased.  But  when  there  is  auricular  fibrillation, — and  auric- 
ular fibrillation  is  more  common  with  mitral  stenosis  than  with 
any  other  lesion  of  the  heart, — the  beneficial  effects  of  digitalis 
far  overshadow  any  possible  disadvantageous  ones. 

In  aortic  stenosis  the  aortic  orifice  is  narrowed  by  thickening 
of  the  valves  or  their  adherence  together,  so  that  the  blood  is 
impeded  in  its  passage  into  the  aorta.  The  result  is  that  the 
systemic  circulation  and  coronary  circulation  tend  to  be  inade- 
quate. In  an  attempt  to  force  more  blood  through  the  narrowed 
orifice  by  an  increased  power  of  systole  the  left  ventricle  is  dilated 
and  hypertrophied.  The  value  of  digitalis  would  not  be  inter- 
fered with  by  such  a  lesion. 

So  much  for  the  heart  lesions.  This  very  brief  review  of 
these  more  common  ones  will  serve  to  indicate  that  great  judg- 
ment must  be  employed  in  the  use  of  digitalis  in  heart  disease. 

But  it  must  not  be  forgotten  that  the  indication  for  digitalis 
is  failure  or  threatened  failure  of  compensation,  and  not  at  all  the 
mere  presence  of  a  valvular  lesion.  When  there  is  poor  compen- 
sation, whether  there  is  a  valvular  lesion  or  not,  digitalis  may  be 
the  best  drug  that  we  can  employ. 


DIGITALIS 


l85 


In  aneurysm  of  the  aorta,  aortitis,  or  arteriosclerosis,  there  is 
no  contraindication  to  digitalis,  so  with  these  lesions,  as  without 
them,  its  use  would  depend  on  the  needs  of  the  heart.  In  pneu- 
monia and  other  acute  infectious  diseases  digitalis  may  be  most 
useful  in  preventing  or  checking  auricular  fibrillation. 

There  is  no  condition  of  the  kidneys,  per  se,  which  calls  for 
digitalis.  Any  striking  diuretic  effect  is  obtained  only  in  condi- 
tions of  venous  engorgement  from  cardiac  failure. 


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Fig.  23. — Case  with  mitral  stenosis  and  auricular  fibrillation.  V.S.,  ventricular 
systole;  R.P.,  radial  pulse.  Digipuratum  reduced  the  pulse  to  normal  rate, 
abolished  the  "pulse  deficit,"  and  increased  the  urinary  flow,  as  shown  above.  At 
the  same  time  there  was  a  very  rapid  and  marked  disappearance  of  dyspnea, 
cyanosis,  and  venous  engorgement.  The  auricle  continued  to  fibrillate  (author's 
case). 

Summary  of  Therapeutics. — 1.  The  indication  for  digitalis 
is  failure  or  threatened  failure  of  compensation.  2.  Its  most 
striking  effects  are  seen  in  auricular  fibrillation  and  when  there  is 
venous  engorgement.     3.  The  drug's  efficiency  is  not  to  be  esti- 


l86  PHARMACOLOGY   AND   THERAPEUTICS 

mated  by  its  effects  on  arterial  pressure.  4.  The  mere  presence 
of  a  valvular  lesion  is  not  a  reason  for  using  digitalis.  5.  The 
diuretic  effect  is  entirely  due  to  improved  circulation,  and  may 
be  evident  even  when  the  heart  weakness  has  not  yet  resulted  in 
obvious  edema  and  dropsy. 

The  Digitalis  Allies. — So  far  as  the  circulation  is  concerned, 
the  uses  of  these  are  the  same  as  those  of  digitalis  itself.  For 
administration  by  mouth  not  one  of  them  has  any  advantage 
over  digitalis  and  its  active  principles.  Convallaria  is  less  cer- 
tain, and  strophanthus  is  prone  to  cause  diarrhea,  while  both 
have  a  smaller  margin  of  safety  between  their  therapeutic  and 
poisonous  doses.  The  difference  between  digitalis  and  stro- 
phanthus in  their  action  upon  the  arteries  is  not  observed 
in  therapeutics. 

But  for  intramuscular  or  intravenous  administration  stro- 
phanthin  and  ouabain  are  the  most  suitable,  and  have  been  used 
with  remarkable,  and  in  some  instances  dramatic,  effects.  For 
intravenous  use,  Bailey  recommends  a  dilution  of  1:8000,  i.  e., 
eV  grain  (0.00 1  gm.)  of  either  principle  in  2  drams  (8  c.c.)  of 
normal  saline.  For  intramuscular  use  he  advises  a  dilution  of 
half  this  strength,  i.  e.,  jfe  grain  in  1  dram  (0.001  gm.  in  4  c.c). 
So  much  as  -gV  grain  (1  mg.)  should  never  be  employed  intra- 
venously at  one  dose  if  the  patient  has  just  previously  been 
taking  any  of  the  drugs  of  the  class  by  mouth.  But  it  may  be 
employed  thirty-six  hours  after  the  last  dose  of  strophanthus  by 
mouth,  or  one  week  after  the  last  dose  of  digitalis.  If  there  is 
any  doubt,  the  beginning  dose  should  not  exceed  yg-g-  grain 
(|-  mg.).     It  may  be  administered  daily  thereafter. 

EPINEPHRINE 

Epinephrine,  more  familiarly  known  by  the  proprietary 
name  adrenaline,  is  an  animal  alkaloid  or  leukomain  obtained 
from  the  medullary  portion  of  the  suprarenal  glands,  chiefly  of 
cattle,  sheep,  and  pigs.  So  far  as  we  know,  it  is  the  same  as  the 
normal  internal  secretion  of  the  gland  in  man.  Its  formula  is 
C6H3(OH)2.CHOH.CH2CH3,  and  it  is  a  distant  relative  of  the 
vasoconstricting  principle  of  ergot,  tyramine.  It  has  the  prop- 
erties of  an  alkaloid,  hence  forms  salts,  is  precipitated  by  alka- 
lies, tannic  acid,  etc.,  and  is  destroyed  by  long  contact  with 
alkalies.  In  the  dried  glands  it  is  present  to  the  extent  of  about 
1  per  cent. 

It  is  marketed  under  several  trade  names,  adrenaline,  supra- 
capsulin,  suprarenalin,  etc.,  in  a  solution  purporting  to  have  a 
strength  of  1  part  of  the  chloride  in  1000.  This  solution  is  not 
decomposed  by  a  moment's  boiling,  so  it  may  be  sterilized  by 


EPINEPHRINE  1 87 

heat.  By  prolonged  boiling  it  is  quite  changed.  On  long 
standing,  or  if  diluted,  it  deteriorates,  slowly  changing  to  a 
reddish  color  and  eventually  precipitating.  It  keeps  better 
when  it  contains  a  slight  excess  of  hydrochloric  acid.  When 
a  precipitate  is  present,  the  solution  should  be  discarded.  Tab- 
lets of  the  hydrochloride,  the  pure  alkaloid,  and  the  tartrate  are 
also  obtainable.  A  synthetic  substitute,  suprarenin,  has  about 
half  the  strength  (Schultz).  It  is  dioxyphenyl-ethanol-methyl- 
amine  chloride. 

The  dried  suprarenal  glands  of  the  sheep  and  ox,  freed  from 
fat,  and  cleaned,  dried,  and  powdered,  are  official  under  the  title 
"Glandulae  Suprarenales  Siccae."  This  dried  gland  is  about  six 
times  as  strong  as  the  fresh  gland,  and  is  used  either  in  tablet 
form  or  in  a  mixture  with  water.  The  latter  must  be  freshly 
prepared,  as  it  does  not  keep. 

Preparations  and  Doses. — The  dose  varies  according  to  the 
method  of  administration  and  the  effect  desired. 

Dried  Suprarenal  Gland. — Dose,  4  grains  (0.25  gm.)  by 
mouth. 

Solution  of  epinephrine  chloride,  1  :  1000,  used  hypodermati- 
cally  in  asthma,  urticaria,  etc.,  15  minims  (1  c.c);  used  intra- 
venously, 2  minims  (0.12  c.c);  or  in  shock,  30  minims  (2  c.c.) 
added  to  saline  and  very  slowly  administered. 

Reid  Hunt,  and  also  Sollmann  and  Brown,  in  1906,  called 
attention  to  the  great  variability  and  poor  keeping  qualities  of 
preparations  of  adrenaline  chloride.  Schultz  (1910)  established 
a  definite  standard  for  assay,  and  on  testing  the  blood-pressure- 
raising  power  of  the  several  commercial  preparations  as  com- 
pared with  pure  solutions  of  epinephrine,  found  them  to  be  of 
variable  efficiency. 

Pharmacology. — General  Action. — Epinephrine  is  a  stimu- 
lant of  sympathetic  nerve-endings  or  their  myoneural  junctions. 
As  Langley  puts  it,  "the  effects  of  adrenaline  upon  any  tissue 
are  such  as  follow  excitation  of  the  sympathetic  nerve  which 
supplies  the  tissue."  The  effects,  so  far  as  muscular  activity  is 
concerned,  depend  upon  the  degree  of  contraction  already  exist- 
ing. Thus,  with  greatly  relaxed  arteries,  the  proportional 
response  is  greater  than  with  arteries  in  normal  contraction;  and 
with  contracted  bronchi  the  relaxation  is  greater  than  in  normal 
bronchi.  Hence  a  dose  which  will  constrict  relaxed  arteries  may 
not  affect  the  bronchi;  and  a  dose  which  will  relax  contracted 
bronchi  may  not  constrict  normal  arteries. 

Skin  and  Mucous  Membranes. — It  has  no  effect  on  the  un- 
broken skin,  but  when  applied  to  cuts,  open  wounds,  ulcers,  or 
any  mucous  membranes  which  can  be  reached  (namely,  those  of 


1 88  PHARMACOLOGY  AND  THERAPEUTICS 

the  conjunctiva,  lacrimal  duct,  nose,  throat,  mouth,  esophagus, 
stomach,  rectum,  vagina,  urethra,  and  bladder),  it  penetrates 
sufficiently  to  stimulate  the  vasoconstrictor  nerve-endings  of  the 
arterioles  at  the  site  of  application.  The  result  is  a  local  con- 
traction of  the  arterioles;  and  this  is  so  marked  that  the  blood  is 
almost  shut  off  from  the  part,  the  tissues  shrink  and  appear 
blanched  from  comparative  bloodlessness,  and  any  moderate 
hemorrhage  is  checked.  This  local  contraction  of  the  arterioles 
is  greater  and  more  prompt  than  from  any  other  drug  in  use.  It 
follows  almost  instantly  the  application  of  the  epinephrine  and 
lasts  from  fifteen  minutes  to  one  or  two  hours.  Repeated  appli- 
cations will  continue  to  keep  the  arterioles  contracted  for  an 
indefinite  length  of  time. 

But  besides  vasoconstriction,  epinephrine  has  also  a  vaso- 
dilator action,  so  that  when  the  application  of  the  drug  is  stopped 
and  the  vasoconstriction  wears  off,  the  arterioles  not  only  relax 
again,  as  usual  after  constriction,  but  may  dilate  away  beyond 
the  normal — in  fact,  may  completely  lose  their  tone,  so  that 
there  may  be  a  late  return  in  marked  degree  of  the  condition 
which  the  epinephrine  was  intended  to  relieve,  viz.,  the  hemor- 
rhage, or  the  congestion,  or  the  relaxed  mucous  membrane. 
Cannon  and  Lyman  (19 13)  bring  forward  some  evidence  against 
this  dilator  effect  being  due  to  stimulation  of  the  vasodilator 
nerves.  In  the  coronary  arteries,  the  dilator  effect  alone  is 
observed,  and  this  is  the  effect  on  other  arteries  after  the  adre- 
naline solution  is  boiled  for  a  length  of  time  (Lieb). 

Absorption  depends  upon  the  method  of  administration — 

1.  Applied  to  mucous  membranes,  or  given  by  mouth,  the 
drug  regularly  has  no  systemic  effect,  or  almost  none.  Possibly 
by  constricting  the  arteries  it  prevents  its  own  absorption.  It  is 
reported  that  an  aqueous  extract  of  two  pounds  of  fresh  supra- 
renal capsules  has  been  swallowed  without  apparent  ill  effect. 
Osborne  and  some  others  claim  that  it  is  slowly  absorbed  from 
the  mouth,  though  not  from  the  stomach,  while  some  have  found 
that  such  large  doses  as  %  ounce  (15  c.c.)  of  the  1  :  1000  epi- 
nephrine solution  in  the  stomach  have  resulted  in  the  character- 
istic effects  on  the  circulation.  A  few  cases  also  are  reported 
of  marked  systemic  effects  from  its  application  to  the  conjunc- 
tiva, the  nose,  and  the  urethra.  But,  as  a  rule,  no  systemic  effect 
at  all  is  obtained  from  the  drug  when  it  is  given  by  mouth  or  applied 
to  mucous  membranes,  and  it  seems  to  be  rapidly  destroyed  at 
the  point  of  entrance  into  the  tissues  before  it  gets  into  the 
circulation. 

2.  From  subcutaneous  injection  there  may  be  a  slight  rise  in 
arterial  pressure,   but  almost  always  there  is  no  measurable 


EPINEPHRINE  1 89 

effect.  This  is  the  author's  experience  in  tests  with  students 
and  asthmatics.  There  is,  however,  a  fairly  prompt  effect  upon 
contracted  bronchi,  even  though  the  arteries  are  unaffected. 

3.  From  deep  intramuscular  injection  enough  seems  to  get 
into  the  blood-stream  to  induce  quite  frequently  a  distinct 
though  comparatively  small  rise  in  arterial  pressure  and  a  re- 
laxation of  the  bronchi.  These  effects  are  most  noticeable  when 
the  arteries  are  relaxed  or  the  bronchi  strongly  contracted. 

4.  From  intravenous  administration  there  is  an  immediate 
and  very  marked  rise  in  arterial  pressure.  This  is  the  only 
method  of  administration  for  a  sure  effect  upon  the  arteries. 

Circulation. — The  effect  of  an  intravenous  dose  upon  the 
circulation  is  a  marked  rise  in  arterial  pressure  and  a  strengthened 
and  slowed  heart.  The  rise  in  pressure  is  only  momentary,  but 
may  be  maintained  by  repeating  the  dose  or  by  continuous  slow 
infusion.  A  graduated  rise  in  pressure  may  be  obtained  by 
intravenous  injection  of  increasingly  large  doses. 

The  Vasoconstriction. — The  most  marked  constriction  is  in 
the  arteries  of  the  splanchnic  area,  where  it  may  be  so  great  that 
the  intestines  are  almost  bloodless.  It  is  produced  if  the  splanch- 
nic nerves  are  cut,  or  if  the  central  nervous  system  is  destroyed; 
therefore  it  is  due  to  a  peripheral  action  and  not  to  a  central  one. 
The  peripheral  effect  is  well  shown  in  an  isolated  viscus  or  an 
isolated  limb,  by  measuring  the  venous  outflow  before  and  after 
epinephrine.  In  perfusing  a  dog's  leg,  for  example,  the  outflow 
may  be  almost  entirely  stopped  by  the  addition  of  a  few  minims 
of  epinephrine  solution  to  the  perfusion  fluid,  but  no  such  action 
occurs  if  apocodeine  or  ergotoxine  has  previously  been  used  to 
paralyze  the  ends  of  the  vasoconstrictor  nerves.  Therefore 
the  site  of  the  stimulation  by  epinephrine  is  the  vasoconstrictor 
nerve-endings  or  the  myoneural  junctions  (Elliott).  After 
ergotoxine,  which  paralyzes  the  vasoconstrictor  endings  but  not 
the  vasodilators,  epinephrine  is  regularly  followed  by  vasodila- 
tion. The  coronary  arteries,  having  no  vasoconstrictor  nerves, 
are  dilated,  or  at  least  their  tone  diminished  so  that  they  become 
dilated  (Janeway  and  Park).  The  cerebral  and  pulmonary 
arteries,  which  also  have  no  vasoconstrictor  nerves,  are  not  con- 
tracted; and  there  is  some  evidence  that  the  cerebral  arteries 
tend  to  be  dilated. 

Janeway  and  Park  (191 2)  have  shown  that  "the  effect  of 
epinephrine  on  an  excised  artery  in  a  physiologically  inert  solu- 
tion is  in  inverse  ratio  to  the  degree  of  tonus  possessed  by  that 
artery."  In  other  words,  it  is  to  be  expected  that  general  arterial 
relaxation  with  low  arterial  pressure,  as  in  Addison's  disease, 
will  give  a  greater  proportionate  response  to  the  drug  than  would 


190  PHARMACOLOGY  AND  THERAPEUTICS 

a  normal  state  of  the  arteries  and  normal  arterial  pressure.  In 
a  case  of  Addison's  disease  at  St.  Luke's  Hospital,  15  minims 
slowly  administered  intravenously  caused  the  pressure  to  rise 
from  90  to  160  mm. 

Cameron  (1906)  determined  that  0.6  mg.  nitroglycerin  was 
just  enough  to  neutralize  the  pressure-raising  power  of  0.0075  mg- 
of  epinephrine  chloride,  i.  e.,  about  8  minims  (0.5  c.c.)  of  the 
1  :  1000  solution. 

The  Slowing. — If  the  vagus  nerves  are  cut,  there  is  no  slowing 
of  the  heart,  or  at  least  if  there  is  slight  slowing,  it  is  abolished  by 
atropine;  therefore  the  slowing  must  be  due  to  stimulation  of  the 
vagus,  and  essentially  of  the  vagus  center.  But  if  the  arterial 
pressure  is  kept  low  by  bleeding  or  by  paralysis  of  the  vasocon- 
strictor endings  by  apocodeine  or  ergotoxine,  there  is  no  slowing. 
It  has  been  shown  also  that  the  slowing  always  follows  the  rise  in 
arterial  pressure.  Thus  it  is  evidently  due  to  the  reflex  stimula- 
tion of  the  vagus  which  regularly  occurs  when  the  arterial  pres- 
sure rises,  and  not  to  direct  stimulation  of  the  vagus  center  by 
the  drug.  Therefore  the  slowing  is  reflex,  and  is  dependent  upon 
the  rise  in  arterial  pressure,  and  not  upon  direct  vagus  stimulation. 

The  Increased  Force  of  the  Heart. — Let  a  heart  be  isolated  so 
as  to  cut  it  off  from  its  central  connections,  and  perfused  with  a 
saline  fluid.  When  epinephrine  is  slowly  added  to  the  perfusion 
fluid,  a  myocardiograph  tracing  shows  increased  systolic  con- 
traction and  lessened  diastolic  relaxation.  In  other  words, 
there  are  increased  contractility  and  increased  tonicity.  Atro- 
pine to  paralyze  the  vagus  endings  does  not  change  the  effect,  but 
apocodeine  and  ergotoxine,  which  paralyze  the  accelerator  end- 
ings, abolish  it.  Therefore  the  accelerator  endings  must  be  the 
site  of  stimulation  by  the  drug.  Some  investigators  believe  that 
there  is  a  slight  muscular  stimulation  in  addition. 

Thus,  in  an  intact  mammal,  epinephrine  slows  the  heart, 
increases  its  tone,  strengthens  its  beat,  and  dilates  its  coronary 
arteries.  It  also  constricts  the  systemic  arterioles.  The  manner 
in  which  these  effects  are  brought  about,  and  the  rapidity  of 
action,  are  entirely  different  from  those  of  digitalis.  The  rise 
in  arterial  pressure  is  very  great  and  very  prompt,  epinephrine 
being  the  most  powerful  blood-pressure-raising  drug  that  we 
employ  in  medicine.  As  the  effect  is  peripheral  and  not  central, 
the  rise  occurs  even  when  the  vasoconstrictor  center  is  paralyzed 
or  exhausted,  but  it  lasts  only  from  one  to  five  minutes.  It  may 
be  kept  up  for  a  long  time  without  apparent  harm  by  frequently 
repeated  doses,  or  by  the  very  slow  administration  intravenously 
of  a  dilution  in  normal  saline  solution. 

From  quickly  repeated  large  doses  the  very  great  constric- 


EPINEPHRINE  IQI 

tion  of  the  arteries  may  result  in  failure  of  the  left  ventricle 
with  dilatation  and  weakness,  at  a  time  when  the  right  heart  is 
pumping  more  blood  into  the  pulmonary  arteries.  The  result  is 
pulmonary  edema.  This  effect  has  frequently  occurred  in  rab- 
bits from  i  or  2  c.c.  of  the  solution.  It  is  especially  likely  to 
occur  when  the  heart  is  already  impaired,  or  if  the  epinephrine 
is  given  with  a  large  saline  infusion,  for  the  saline  liquid  adds 
to  the  diffusible  fluid  in  the  lung  capillaries. 

Blood. — Richards  and  Vosburgh  have  reported  that  adrena- 
line increases  the  coagulability  of  the  blood,  a  property  which 
might  add  to  the  power  of  the  drug  to  check  hemorrhage.  Wig- 
gers  has  been  unable  to  confirm  their  observation. 

Internal  Hemorrhage. — Wiggers  has  shown  that  pulmonary 
hemorrhage  is  increased,  as  might  be  surmised  from  the  known 
failure  of  the  drug  to  constrict  the  pulmonary  arteries;  also  that 
intestinal  or  renal  hemorrhage  may  sometimes  be  checked  by  the 
great  contraction  of  the  splanchnic  arteries.  But  the  effective 
dose  is  uncertain,  and  too  large  a  dose  will  increase  the  hemor- 
rhage; therefore  it  cannot  safely  be  employed  in  therapeutics  to 
check  internal  hemorrhage. 

Connective-tissue  Changes  in  the  Heart  and  Arteries. — In  1903 
Josue  described  sclerotic  lesions  of  the  aorta  in  rabbits  to  which 
adrenaline  had  been  administered  intravenously  for  long  periods. 
In  1906  Pearce  and  Stanton  injected  3  minims  of  the  1  :  1000 
solution  every  day  for  two  months,  and  obtained  not  only  these 
aortic  changes,  which  they  observed  to  be  due  to  degeneration 
and  calcification  in  the  muscular  tissue  of  the  media,  but  noted 
also  bulging  of  these  weakened  areas,  the  mechanical  breaking  of 
the  elastic  fibers,  and  the  actual  formation  of  aneurysmal  dilata- 
tions. Pearce  noted,  also,  some  connective-tissue  changes  in 
the  myocardium,  but  none  in  the  peripheral  arteries,  while  Erb 
found  arteriosclerotic  changes  in  the  other  arteries  as  well  as  the 
aorta.  Erb  attributes  the  effects  to  a  toxic  action  rather  than  to 
the  heightened  blood-pressure,  for  he  obtained  them  by  intra- 
peritoneal injections  which  did  not  raise  blood-pressure.  The 
lesions  in  adrenaline-produced  arterioscleroses  differ  pathologi- 
cally from  the  lesions  of  arteriosclerosis  in  human  beings,  but 
furnish  valuable  material  for  study.  Pearce  and  Hill  have 
later  questioned  the  role  of  adrenaline  in  the  production  of  some 
of  these  results,  as  they  found  arteriosclerotic  changes  quite 
common  in  supposedly  normal  rabbits. 

The  fear  of  producing  any  such  changes  by  the  therapeutic 
use  of  the  drug  need  not  be  great,  for  we  never  administer  adre- 
naline repeatedly  for  long  period  except  in  two  conditions,  viz., 
disease  of  the  suprarenal  glands  and  bronchial  asthma.     The 


192  PHARMACOLOGY  AND  THERAPEUTICS 

former  is  so  regularly  fatal  that  any  risk  may  be  taken  for  the 
chance  of  helping;  moreover,  the  theory  upon  which  adrenaline 
is  given  is  that  it  may  make  up  for  a  pathologic  deficiency  of  the 
natural  adrenaline  of  the  patient,  and,  therefore,  cannot  be 
present  in  the  system  in  excess.  This  theory  is  believed  to  be 
incorrect.  (See  Therapeutics.)  In  intractable  bronchial  asthma 
the  drug  may  be  used  repeatedly  by  hypodermatic  injection 
during  long  periods,  and  it  is  well  in  these  cases  to  think  of  the 
possibility  of  harm  to  the  arteries  and  heart. 

Respiratory  System. — Used  hypodermatically  in  small  quan- 
tities, epinephrine  causes  increased  depth  of  respiration;  while 
if  it  is  used  intravenously  it  quickens  respiration,  the  inspirations 
being  shallower.  Park  (191 2)  found  that  when  it  was  applied 
to  excised  rings  of  the  bronchi  of  the  ox,  even  in  a  concentration 
as  low  as  1  :  10,000,000,  it  regularly  caused  relaxation  without 
primary  constriction.  And  it  may  be  presumed  that  this  effect 
is  due  to  stimulation  of  the  bronchodilator  (sympathetic)  nerve- 
endings.  In  man,  when  it  is  given  hypodermatically,  it  produces 
a  decided  relaxation  of  contracted  bronchi.  The  rule  that  the 
drug  acts  best  where  the  condition  it  is  opposing  is  extreme, 
makes  it  peculiarly  valuable  in  spasmodic  asthma  due  to  exces- 
sive bronchial  contraction,  for  the  effect  on  the  bronchi  is  out  of 
proportion  to  the  effect  elsewhere,  and  is  often  evident  even 
when  the  arterial  pressure  is  not  affected  in  measurable  degree. 

Nervous  System. — Following  a  hypodermatic  dose,  as  for 
asthma,  there  is  frequently  an  immediate  onset  of  nervous  excite- 
ment and  restlessness  which  may  last  as  much  as  an  hour  or  two. 

Alimentary  Tract. — The  local  astringent  effects  may  be 
obtained  in  mouth,  esophagus,  stomach,  and  rectum.  On 
intravenous  injection  the  drug  stimulates  the  ends  of  the  splanch- 
nic or  inhibitory  nerves  (which  belong  to  the  sympathetic 
system),  and  so  lessens  peristalsis  of  stomach  and  bowels.  The 
contractions  of  the  gall-bladder  are  said  to  be  inhibited  in  the 
same  way.  The  mucous  secretions,  the  saliva,  and  the  bile  are 
increased,  as  mentioned  above.  Pemberton  and  Sweet  (191 2) 
have  shown  that  intravenous  injections  of  epinephrine  inhibit 
the  flow  of  pancreatic  juice;  and  Herter  found  that  painting  the 
pancreas  with  epinephrine  resulted  in  glycosuria. 

The  Eye. — A  drop  of  epinephrine  solution  in  the  eye  causes 
the  conjunctiva  to  become  shrunken  and  pale,  the  eyelids  to 
become  retracted,  and  the  eyeball  to  appear  more  prominent. 
The  drug,  if  in  strong  solution,  also  penetrates  to  the  internal  eye, 
and  by  stimulation  of  the  sympathetic  nerve-endings  in  the 
libers  of  its  radial  muscles  dilates  the  pupil.  A  solution  of 
1  :  1000  ordinarily  does  not  dilate  the  human  pupil  or  that  of  the 


EPINEPHRINE  1 93 

dog;  but  in  the  dog  it  does  so  after  extirpation  of  the  pancreas 
(Loewi),  and  in  human  cases  may  do  so  in  hyperthyroidism, 
pancreatic  disease,  and  states  of  abnormal  excitement  of  the 
sympathetic  nervous  system.  The  failure  of  the  human  pupil 
to  dilate  from  a  i  per  cent,  solution  means  paralysis  of  the  sympa- 
thetic nerves  to  the  eye.  As  a  test  for  adrenaline  in  a  liquid, 
Meltzer  and  Auer  make  use  of  the  extirpated  frog's  eye,  which 
regularly  reacts  to  a  strength  of  i  :  iooo,  or  even  of  i  :  10,000. 

Muscle. — The  contraction  of  striped  muscle  is  not  affected, 
but  its  relaxation  is  greatly  slowed,  as  with  veratrine.  Smooth 
muscle  shows  the  effects  of  stimulation  of  sympathetic  nerve- 
endings. 

Secretions. — The  tears,  saliva,  bile,  and  mucus  are  increased 
by  stimulation  of  the  sympathetic  nerve-endings  in  the  glands. 

Uterus. — Epinephrine  causes  constriction  of  the  uterine 
arteries  and  of  the  uterus  itself.  The  latter  effect  also  follows 
local  application  (as  in  an  intra-uterine  douche). 

Bladder. — Local  application  produces  an  astringent  effect 
upon  the  bladder-wall.  Intravenous  administration  results  in 
stimulation  of  the  ends  of  the  sympathetic  or  inhibitory  nerves 
of  the  bladder,  with  the  effect  of  relaxation  of  the  bladder  mus- 
cles.    The  ureter  is  contracted. 

Urine. — The  secretion  of  urine  is  increased  synchronously 
with  the  rise  in  arterial  pressure,  and  continues  above  normal  for 
several  minutes  after  blood-pressure  falls.  It  is  believed  that 
the  kidney  arteries  are  passively  dilated.  In  five  experiments 
by  Houghton  the  arterial  pressure  averaged  a  rise  of  from  56  to 
88  mm.  Hg,  and  the  urine  an  increase  of  from  8  to  30  minims. 
But  the  arterial  pressure  averaged  six  minutes  for  its  return  to 
normal,  while  the  urine  secretion  did  not  get  back  to  normal 
until  fifteen  minutes.  It  is  an  interesting  observation  that  the 
urine  may  be  found  to  contain  sugar,  and  this  has  been  proved  to 
be  due  to  an  excessive  amount  of  sugar  in  the  blood  from  lack  of 
dextrose  destruction.  It  is  an  artificial  diabetes,  which  occurs 
even  if  the  rise  in  blood-pressure  is  prevented.  It  does  not  occur 
if  the  animal  is  first  starved  until  its  stored  glycogen  is  all  used 
up.  Herter  and  his  associates  have  found  that  the  same  effect 
follows  when  the  pancreas  is  painted  with  epinephrine. 

Elimination. — The  fate  of  epinephrine  is  not  certainly  known. 
Falta  says  that  when  it  is  injected  subcutaneously  or  into  the 
peritoneal  cavity,  none  appears  in  the  urine,  while  when  given  by 
mouth,  though  it  has  no  systemic  effects,  it  is  eliminated  in  the 
urine. 

Tolerance. — Repeated  injections  induce  a  certain  tolerance 
(Paton). 
13 


194  PHARMACOLOGY   AND    THERAPEUTICS 

Toxicology. — From  the  local  use  of  the  drug,  there  have  been 
reports  of  overacting  heart,  palpitation,  and  vomiting.  These 
must  be  due  to  idiosyncrasy,  for  they  are  unusual.  After  the 
hypodermatic  or  intravenous  doses  there  is  frequently  excitement, 
with  tremor,  and  in  some  cases  much  anxiety.  Cushny  says 
that  the  hypodermatic  injection  of  very  large  closes  in  mammals 
results  in  excitement,  tremors,  and  paralysis  of  the  hind  limbs, 
and,  in  addition,  sometimes  vomiting,  increased  urination,  or 
hemorrhages  from  various  mucous  membranes  or  from  the  kid- 
neys. Death  occurs  either  from  paralysis  of  the  respiratory 
center  or  from  heart  failure,  due  to  back  pressure  from  the 
constricted  systemic  arteries.  There  is  no  doubt  that  some 
post-operative  cases  of  pulmonary  edema  are  due  to  the  use  of 
this  drug  with  saline  infusion. 

Epinephrine  and  Chloroform. — Levy  and  Lewis  (191 2)  report 
a  research  on  cats,  regarding  the  simultaneous  use  of  these  two 
drugs.  They  found  that — (1)  Small  intravenous  injections  of 
epinephrine  chloride,  given  to  an  animal  under  high  percentages 
of  chloroform  vapor,  produce  a  condition  of  irritability  of  the 
ventricle  with  irregular  and  rapid  heart;  and  that  (2)  low  ten- 
sions of  chloroform  vapor  with  small  intravenous  injections  of 
epinephrine  chloride  ultimately  produce  the  highest  grade  of 
ventricular  disorder,  viz.,  ventricular  fibrillation,  which  means 
death.  These  effects  have  been  denied,  and  corroboration  is 
needed. 

Therapeutics. — A.  For  local  effect  it  is  employed — 1.  To 
cause  shrinkage  of  mucous  membrane,  whether  the  membrane  is 
normal  or  swollen  and  hyperemic.  In  the  nose  such  shrinkage 
gives  a  clearer  view  for  examinations,  and  more  room  for  the 
passage  of  instruments,  such  as  a  Eustachian  catheter.  In  hay- 
fever  or  acute  catarrh,  i.  e.,  a  fresh  cold  in  the  head,  the  applica- 
tion of  an  epinephrine  solution  on  a  cotton  probe  almost  instantly 
shrinks  the  tissues  and  frees  the  stuff ed-up  air-passages.  This 
effect  may  last  half  an  hour  or  more,  and  if  the  patient  then 
remains  quiet  and  in  a  warm  room,  may  persist  for  hours  after 
the  adrenaline  action  is  over.  In  hay-fever  the  adrenaline  solu- 
tion diluted  with  normal  saline  is  often  used  as  a  spray;  but  it 
might  be  noted  that  there  are  some  reports  of  chronic  turgescence 
or  hyperemia  following  its  frequent  use  in  this  condition.  In 
some  operations,  as  for  adenoids  and  hypertrophies,  the  shrink- 
age of  tissue  may  be  undesirable.  Dropped  in  the  eye,  it  may 
lessen  a  conjunctival  swelling,  and  so  favor  the  finding  and 
removal  of  a  foreign  body.  In  prolapse  of  the  rectum,  or  hemor- 
rhoids, the  shrinkage  may  enable  the  protruding  mass  to  be 
replaced. 


EPINEPHRINE  1 95 

2.  To  arrest  a  small  hemorrhage — at  any  place  where  the  bleed- 
ing point  is  accessible,  as  in  the  nose,  stomach,  bladder,  etc.  In 
nose-bleed  the  hemorrhage  may  often  be  checked  by  a  pledget  of 
cotton  soaked  in  epinephrine  solution  and  applied  to  the  bleeding 
spot.  In  postpartum  hemorrhage  the  liquid  may  be  added  to 
a  hot  intra-uterine  injection  to  favor  uterine  contraction  and 
perhaps  to  constrict  the  uterine  arteries. 

3.  To  prolong  local  anesthesia  and  to  prevent  local  hemorrhage — 
it  is  added  to  solutions  of  cocaine  and  other  local  anesthetics. 
It  acts  by  vasoconstriction,  which  checks  the  rapid  removal  of 
the  anesthetic  by  the  blood-stream.  Berry  (1905)  showed  that 
the  toxic  action  of  cocaine  is  increased  when  it  is  administered 
with  adrenaline. 

4.  To  allay  itching  of  vulva  and  anus  it  may  be  applied  on 
cotton.  It  acts  on  the  moist  parts  of  the  vulva,  whether  mucous 
membrane  or  not. 

5.  In  anterior  poliomyelitis,  in  the  ascending  paralysis  types, 
spinal  injection  of  15  minims  (1  c.c.)  has  seemed  to  check  the 
progress  of  the  paralysis. 

B.  For  systemic  efect — it  is  administered  hypodermatically 
or  intravenously,  according  to  the  condition  to  be  treated. 

1.  Hypodermatically — (a)  to  overcome  bronchial  asthma,  a 
single  dose  of  15  minims  (1  c.c),  and  (b)  in  Addison's  disease, 
5  minims  (0.3  c.c),  three  times  a  day.  This  latter  is  a  condition 
of  weakness  and  wasting,  with  pigmentation  of  the  skin  and  low 
blood-pressure;  and  it  results  from  destruction  of  the  suprarenal 
glands.  It  was  thought  that  doses  of  epinephrine  might  take 
the  place  of  the  natural  secretion  of  these  glands,  but  reports 
from  its  use  hypodermatically  or  by  mouth  are  not  encouraging, 
and  intravenous  administration  several  times  a  day  in  chronic 
disease  is  obviously  impossible.  In  our  own  experience  there 
has  been  no  effect  on  the  course  of  the  disease,  the  circulation, 
or  the  general  weakness.  Others  report  temporary  improvement. 
Osborne  recommends  the  whole  gland  in  the  form  of  tablets 
which  are  allowed  to  disintegrate  slowly  in  the  mouth.  As  a 
matter  of  fact,  recent  research  would  seem  to  indicate  that  the 
manifestations  of  Addison's  disease  are  not  due  merely  to  ab- 
sence of  epinephrine,  but  also  to  the  loss  of  one  or  more  elements 
from  the  cortex  of  the  gland ;  and  this  would  account  for  the  lack 
of  benefit  from  the  administration  of  epinephrine. 

2.  Intravenously — it  is  employed  as  a  rapidly  acting  circula- 
tory stimulant  of  great  power  in  collapse  or  shock.  Owing  to  its 
ephemeral  action  and  to  the  impracticability  of  frequent  intra- 
venous doses,  it  is  suitable  only  in  emergencies,  and  is  not  em- 
ployed in  ordinary  conditions  of  failure  of  compensation.     For 


196  PHARMACOLOGY  AND  THERAPEUTICS 

administration,  it  may  be  diluted  with  normal  saline  and  injected 
into  the  vein  by  a  syringe;  if  there  has  been  loss  of  blood,  it  may 
be  added  to  a  saline  infusion.  If  given  rapidly  with  a  saline 
infusion  when  there  has  been  no  loss  of  blood,  it  increases  the 
chances  of  pulmonary  edema  and  heart  failure,  but  a  good-sized 
dose  may  be  given  with  saline  if  the  infusion  is  carried  on  very 
slowly.  Small  doses,  but  not  large  ones,  may  be  of  value  in 
intestinal  hemorrhage,  for  they  tend  to  constrict  the  intestinal 
arteries  out  of  proportion  to  the  general  rise  in  arterial  pressure 
(Wiggers),  but  the  effective  dose  is  very  uncertain. 

Dangers. — A.  From  Local  Use. — 1.  After  operations  (upon 
the  nose,  urethra,  etc.)  there  is  risk  of  late  hemorrhage  from 
secondary  vasodilatation. 

2.  In  hay-fever  there  is  risk  of  a  chronic  state  of  vascular 
dilatation  following  the  frequent  use  of  the  drug. 

B.  From  Intravenous  Administration. — 1.  In  cerebral  arterio- 
sclerosis there  is  risk  of  rupture  of  a  cerebral  artery  from  any 
sudden  great  rise  in  general  blood-pressure. 

2.  In  internal  hemorrhage,  especially  cerebral  or  pulmonary, 
there  is  risk  of  increasing  the  hemorrhage. 

3.  In  pulmonary  edema  there  is  risk  of  increasing  the  edema. 

4.  In  emergencies  there  is  risk  of  precipitating  heart  failure 
and  producing  pulmonary  edema  or  general  edema. 

PITUITARY   EXTRACT 

This  substance  is  an  extract  from  the  infundibular  (posterior) 
portion  of  the  pituitary  body.  So  far  it  has  yielded  no  active 
principle.  The  extract  will  not  prevent  the  effects  of  the  removal 
of  the  gland  on  growth  and  development.  These  are  presumably 
controlled  by  the  anterior  lobe.  In  acromegaly  the  symptoms 
may  be  enhanced  rather  than  prevented  by  the  administration 
of  pituitary  extract,  and  this  would  fit  the  theory  that  acromegaly 
is  due  to  overactivity  rather  than  underactivity  of  the  gland. 
The  preparations  on  the  market  are  employed  in  doses  of  1  c.c. 
hypodermatically.     Schaefer  attributes  its  effects  to  a  hormone. 

Circulation. — The  striking  feature  of  pituitary,  both  from  its 
local  application  and  when  it  is  injected  into  a  vein,  is  its  seem- 
ing similarity  in  action  to  epinephrine.  The  local  application 
results  in  local  constriction  of  the  arteries;  the  intravenous 
administration  induces  slowing  and  strengthening  of  the  heart 
and  a  rise  in  arterial  pressure.  The  action  of  pituitary  extract 
begins  in  a  minute  or  less,  and  the  maximum  rise  in  pressure 
sometimes  equals  that  from  epinephrine,  though  it  is  more 
slowly  attained.  The  return  to  normal  occupies  usually  from 
five  to  ten  minutes,  i.  e.,  about  two  or  three  times  as  long  as  that 


PITUITARY    EXTRACT 


197 


of  epinephrine.  Occasionally  the  action  lasts  as  much  as  half 
an  hour. 

But  there  is  a  marked  difference  in  the  site  of  action  from 
that  of  epinephrine,  for  the  slowing  of  the  heart  takes  place  after 
atropine,  and  is,  therefore,  a  muscular  and  not  a  vagus  effect;  and 
Wiggers,  and  also  McCord,  have  shown,  by  perfusion  experiments, 
that  after  apocodeine  or  ergotoxin,  while  epinephrine  has  no  vaso- 
constrictor action  at  all,  pituitary  extract  constricts  the  vessels  as 
much  as  it  did  before.  Also,  pituitary  constricts  the  coronary,  pul- 
monary, and  cerebral  arteries.  Hence  it  must  act  by  stimulating 
the  muscles  of  the  arteries  and  not  the  vasoconstrictor  nerve- 
endings.     Wiggers  recommends  it  in  pulmonary  hemorrhage. 

With  isolated  arteries  the  doses  may  be  repeated  indefinitely, 
and  vasoconstriction  is  always  the  result.  But  McCord  reports 
that,  in  the  intact  animal,  after  several  repetitions  of  the  dose, 
the  arterial  pressure  falls.  This  fall  has  been  shown  by  McCord 
to  be  due  neither  to  lessened  output  of  the  heart  nor  to  a  central 
dilating  influence,  but  to  the  conversion  of  the  constrictor  action 
into  a  peripheral  dilator  effect  on  the  wall  of  the  vessels.  This 
action  results  when  the  pituitary  reaches  a  certain  concentration 
in  the  blood.  But  Lieb  and  Bastedo  failed  to  get  any  dilator 
effect  from  nine  successive  large  doses. 

Splanchnic  Organs. — In  perfusing  the  isolated  kidney  in  an 
oncometer,  the  addition  of  pituitary  regularly  results  in  a  shrink- 
age in  size  and  a  lessened  venous  output;  but  with  the  kidney  of 
an  intact  animal,  the  volume  is  increased  (sometimes  after  pre- 
liminary shrinkage),  and  there  is  increased  venous  output  and 
increased  urination  (Wiggers,  191 1).  Sollmann  and  Pilcher 
have  shown  that,  so  far  as  the  vessels  of  the  spleen  are  concerned, 
there  is  a  central  vasodilator  action,  and  McCord  has  been  able 
to  demonstrate  the  same  action  on  the  kidney  vessels.  The 
intestinal  muscles  are  also  stimulated  and  peristalsis  increased. 

Uterus. — The  stimulating  action  on  smooth  muscle  extends 
to  the  uterus,  and  in  dose  of  15  minims  (1  c.c.)  the  drug  has 
recently  been  given  by  deep  intramuscular  injection  for  menor- 
rhagia,  subinvolution,  and,  at  the  time  of  labor,  for  uterine 
inertia.  Cases  of  dangerous  constriction  from  this  have  been 
reported.  Hauch  and  Meyer  (191 2)  warn  against  its  use  in 
cases  with  high  arterial  tension.  B rammer  noted  such  violent 
contractions  of  the  uterus  in  one  case  that  he  had  to  administer 
chloroform.     Schaefer  says  it  also  increases  the  secretion  of  milk. 

Internal  Secretions. — In  hyperthyroidism,  pituitary  has  at 
times  seemed  to  lessen  the  excessive  thyroid  secretion,  with 
disappearance  of  the  acute  symptoms.  It  tends  to  inhibit  the 
flow  of  pancreatic  juice  (Wiggers). 


198  PHARMACOLOGY  AND  THERAPEUTICS 

Toxicity. — Experiments  by  Houghton  would  indicate  its 
comparative  freedom  from  poisonous  properties,  for  after  15  c.c. 
by  mouth,  or  3  c.c.  hypodermatically,  guinea-pigs  of  400  gm. 
weight  showed  no  toxic  symptoms.  Yet  the  author  has  seen 
manifestations  of  overexcitability  of  the  heart  in  dogs  in  the 
form  of  premature  beats,  and  has  noted  skipped  beats  of  both 
auricle  and  ventricle. 

Therapeutics. — Its  uses  have  not  yet  been  well  defined,  and 
are — (1)  Intravenously  in  shock;  (2)  hypodermatically  in  uterine 
inertia,  and  perhaps  (3)  in  pulmonary  hemorrhage,  and  (4)  in 
intestinal  paralysis. 

BARIUM 

The  common  soluble  salts  of  barium  (barium,  barii)  are 
the  chloride  and  the  nitrate,  dose,  1  grain  (0.06  gm.).  They 
are  little  employed  except  in  pharmacologic  laboratories  and  in 
veterinary  practice.  Barium  has  recently  been  found  in  the 
western  "loco-weed"  (mad- weed),  which  causes  hallucinations 
and  destruction  in  cattle;  but  Alsberg  and  Black  believe  it  to 
be  present  in  too  small  quantity  to  be  responsible  for  the  "loco1' 
disease. 

Barium  is  locally  irritant  and  is  a  powerful  direct  stimulant 
of  all  forms  of  muscle.  Smooth  muscle  may  go  into  tonic  con- 
traction, while  striped  muscle  shows  increased  contraction  and  a 
prolonged  time  for  relaxation — the  so-called  veratrine  action. 
The  contraction  is  more  deliberate  than  that  produced  through 
nerve  stimulation.  Absorption  is  so  slow  that  the  drug  acts  as  a 
cathartic,  the  chloride  being  used  for  this  purpose  in  veterinary 
practice.  From  excessive  muscular  contraction  there  may  be 
vomiting,  diarrhea,  or  colic.  Barium  sulphate  is  bland  and  has 
been  employed  to  outline  the  alimentary  tract  for  x-ray  pictures. 

Circulatory  System. — As  the  result  of  direct  stimulation  of 
the  heart  muscle,  the  systolic  contraction  is  more  complete  and 
the  diastolic  relaxation  less  so,  and  this  tendency  may  progress 
until  but  little  blood  is  expelled  at  each  systole.  After  death,  the 
frog's  heart  is  firmly  contracted  in  systole.  The  arterioles, 
including  the  pulmonary,  cerebral,  and  coronary,  which  have  no 
vasoconstrictor  nerves,  are  strongly  contracted  from  muscular 
stimulation;  and  characteristically  the  contraction  develops  more 
slowly  and  is  of  longer  duration  than  arterial  contraction  brought 
about  by  impulses  through  the  vasoconstrictor  nervous  mecha- 
nisms. 

The  uterus,  the  bladder,  and  other  organs  are  also  strongly 
contracted.  There  are  some  peculiar  effects  upon  the  central 
nervous  system,  resulting  in  hallucinations  and  other  "loco" 


CAMPHOR  199 

phenomena,  and  death  is  preceded  by  tonic  and  clonic  convul- 
sions. The  chemic  antidote  in  the  alimentary  tract  is  any  sol- 
uble sulphate,  for  this  forms  the  insoluble  barium  sulphate.  It 
should  be  removed  from  the  stomach  by  lavage  or  an  emetic. 
The  systemic  treatment  of  poisoning  is  symptomatic,  the  nitrites 
being  the  best  drugs  to  counteract  the  general  vasoconstriction. 

CAMPHOR 

Camphor  (camphora,  ae)  is  a  stearopten,  C9Hi6CO,  which  is 
chemically  a  ketone.  It  is  made  synthetically  or  is  obtained  by 
boiling  the  twigs  and  wood  of  Cinnamomum  camphora  (Fam. 
Lauraceoe)  with  water,  and  condensing  the  distillate.  The  cam- 
phor tree  is  an  evergreen  of  Japan  and  China,  and  has  been  intro- 
duced into  the  southern  United  States  for  ornamental  purposes. 
Camphor  is  a  volatile,  inflammable,  gummy  substance,  freely 
soluble  in  alcohol,  ether,  chloroform,  and  the  fixed  and  volatile 
oils.  In  water  it  is  soluble  to  the  extent  of  about  8  parts  in  1000, 
just  enough  to  impart  to  the  water  a  strong  odor  and  taste. 
Though  of  a  gummy  nature,  it  may  be  powdered  on  the  addition 
of  a  little  alcohol  or  chloroform.  Its  mixtures  with  menthol, 
salol,  chloral  hydrate,  thymol,  and  some  other  solids  become 
liquid  without  apparently  undergoing  any  chemic  change. 

Preparations  and  Doses. — 
Camphor,  2  grains  (0.13  gm.). 
Water,  0.8  per  cent.,  2  drams  (8  c.c). 
Spirit,  10  per  cent.,  20  minims  (1.3  c.c). 
Liniment  (camphorated  oil),  20  per  cent. — for  external  use. 
Cerate  (camphor  ice),  2  per  cent. — for  external  use. 

Camphor  is  also  an  ingredient  of  soap  liniment,  chloroform 
liniment,  menthol-camphor,  N.  F.  (menthol,  1;  camphor,  1), 
chloral-camphor,  N.  F.  (chloral  hydrate,  1;  camphor,  1),  and 
various  diarrhea  remedies.  Among  these  latter,  two  well- 
known  ones  are  "Sun  Cholera  Drops"  and  " Squibb 's  Diarrhea 
Mixture."  (See  Anti-diarrheics.)  An  allied  product  is  mono- 
bromated camphor  (camphora  monobromata) ,  i.  e.,  camphor  in 
which  one  H  has  been  replaced  by  bromine,  C9Hi5BrCO.  It 
is  used  for  its  bromine  as  a  nerve  sedative,  dose,  2  grains  (0.13 
gm.). 

Pharmacologic  Action. — Micro-organisms  and  Insects. — Cam- 
phor is  moderately  antiseptic.  Its  odor  is  disliked  by  insects, 
and  it  is  used  to  drive  away  moths,  mosquitos,  etc. 

Skin. — If  a  strong  preparation  is  rubbed  into  the  skin  or 
kept  in  contact  with  it  for  some  time,  it  is  counterirritant,  exert- 
ing a  "  rubefacient "  effect,  i.  e.,  it  irritates  the  skin  and  dilates 
the  skin-vessels  so  that  the  part  becomes  red  and  warm.     It 


200  PHARMACOLOGY  AND   THERAPEUTICS 

should  be  covered  with  a  piece  of  flannel  or  oiled  silk  to  prevent 
evaporation.  If,  however,  camphor  dissolved  in  alcohol,  as  in 
spirit  of  camphor,  is  applied  and  allowed  to  evaporate,  it  has 
just  the  opposite  effect,  that  is,  blanches  and  cools  the  part. 

Mucous  Membranes. — Camphor  irritates  mucous  membranes 
and  causes  them  to  contract,  and  for  this  and  its  antiseptic 
property  is  considered  useful  in  nasal  therapeutics. 

Alimentary  Tract. — The  solid  gum-camphor  is  chewed  with 
pleasure  by  some  people,  but  to  most  has  a  biting  taste  and  is 
nauseating.  In  solution  it  has  a  strongly  carminative  action, 
and  in  strong  doses  may  be  so  irritant  as  to  cause  vomiting.  In 
the  intestines  it  is  believed  to  check  secretion,  though  this  point 
is  not  definitely  established.  It  is  said  also  to  be  antiseptic  in 
the  intestines,  because  in  a  series  of  tests  it  was  shown  to  decrease 
the  ethereal  sulphates  of  the  urine. 

Absorption. — It  is  absorbed  readily  from  stomach  and  intes- 
tines, and,  if  used  hypodermatically,  from  the  tissues.  When 
used  hypodermatically,  it  is  irritant. 

Circulatory  Organs. — Before  Absorption. — When  the  drug  is 
swallowed  in  strong  enough  solution  to  have  marked  local  action 
on  the  mouth,  there  is  at  once  a  moderate  acceleration  of  the 
rate  of  the  heart  corresponding  with  that  obtained  from  other 
members  of  the  volatile  oil  series.     It  is  solely  a  reflex  effect. 

After  Absorption. — Any  good  effects  upon  the  circulation  are 
extremely  problematic,  the  ones  reported  being  mild  stimulation 
of  the  heart  muscle  and  mild  stimulation  of  the  vagus  and  vaso- 
constrictor centers.  In  normal  animals  the  rate  and  force  of 
the  heart  continue  about  the  same,  and  the  total  output  of  the 
heart  is  either  not  affected  at  all  or  is  slightly  increased.  There 
is  also  a  dilatation  of  the  skin-vessels,  but  this  does  not  essen- 
tially affect  general  arterial  pressure. 

The  stimulation  of  the  vasoconstrictor  center  is  an  uncertain 
quantity,  for  at  times  there  is  no  stimulation;  while  when  there 
is  stimulation,  it  may  be  intermittent,  so  that  periods  of  lowered 
arterial  pressure  alternate  with  periods  of  raised  arterial  pressure. 
There  may  be  slowing  of  the  heart  and  a  fall  in  blood-pressure. 
Hence,  as  a  vasoconstrictor,  camphor  ranks  low.  Cushny  says 
of  it,  "in  man  and  animals  the  heart  is  sometimes  slowed,  but  is 
generally  little  affected  in  either  strength  or  rate,"  and,  "the 
slight  dilatation  of  the  vessels  (of  the  skin)  is  the  only  change 
in  the  circulation,  unless  quantities  sufficient  to  cause  con- 
vulsions are  injected."  Gottlieb  and  Meyer  (1910)  agree  with 
Cushny  so  far  as  normal  laboratory  animals  are  concerned. 
"Thus,"  they  say,  "camphor  cannot  ordinarily  be  considered  a 
circulatory   stimulant.     But   in   the   conditions   of   circulatory 


Aur. 


Ven. 


Fig.  27. — Camphor  in  oil,  20  mg.  per  kilo  intravenously.  Little  effect  on 
auricle  and  ventricle.  Fall  in  arterial  pressure  from  91  to  78.  Pulse  somewhat 
slowed.     (Tracing  made  by  Dr.  C.  C.  Lieb.) 


CAMPHOR  20I 

failure,  where  stimulus  production  in  the  heart  threatens  to  fail, 
camphor  is  undoubtedly  to  be  considered  a  heart  stimulant. 
For  in  perfusion  camphor  will  overcome  the  fibrillation  of  the 
auricle  which  is  caused  by  chloroform  and  other  poisons,  and 
even  that  from  electric  stimulation,  and  it  will  prevent  the  excess- 
ive slowing  and  weakening  brought  on  by  chloral  hydrate." 
Heinz  says  practically  the  same. 

In  one  case  of  septicemia  in  which  the  author  injected  5 
grains  (0.3  gm.)  of  camphor  in  oil  hypodermatically  three  times 
a  day  for  two  days  there  occurred,  on  three  occasions,  for  about 
two  hours  after  the  dose,  a  distinct  weakening  of  the  heart,  with 
depression  of  the  respiration  and  Cheyne-Stokes  breathing. 

Heard  and  Brooks  (1913)  tested  camphor  on  human  beings. 
In  5  cases  with  normal  circulation  a  hypodermatic  of  camphor, 
20  grains  (1.3  gm.)  in  oil,  showed  in  four  no  change  in  the  circula- 
tion, and  in  the  other  one  a  fall  of  17  mm.  in  systolic  and  25  mm. 
in  diastolic  pressure.  In  9  cases  with  auricular  fibrillation  and 
other  cardiovascular  conditions  there  was  no  change,  except  in 
2  of  them  a  very  slight  rise  in  pressure.  Their  observations 
were  made  for  from  forty  to  two  hundred  and  seventy  minutes 
after  the  injection.  The  only  rises  in  pressure  were  in  cases  with 
great  mental  excitement,  and  in  these,  on  a  second  test,  there 
was  no  rise.  Even  as  much  as  50  grains  (3.3  gm.)  failed  to  pro- 
duce any  definite  effects,  either  desirable  or  toxic.  In  perfusing 
a  cat's  isolated  heart,  camphor  in  saturated  solution  was  without 
effect  on  the  normal  heart,  but  in  2  instances  checked  experi- 
mental fibrillation. 

We  do  not  think  it  should  be  used  as  a  heart  stimulant  at  all, 
except  as  a  single  dose  in  emergency.  Even  then  it  is  entirely 
unreliable. 

Respiratory  Organs. — As  with  other  carminatives,  there  is 
a  reflex  stimulation  from  the  stomach  or  mouth.  Systemically, 
after  large  doses,  there  is  some  stimulation  of  the  respiratory 
center.  It  is  thought  that  some  of  the  drug  is  eliminated  in 
the  bronchial  mucus;  but  if  this  is  so,  the  dose  of  2  grains  or 
thereabouts  is  too  small  for  any  effective  remote  local  action. 

Cerebrum. — Given  by  mouth,  camphor  tends  to  lessen  hys- 
teric excitement  and  nervous  instability.  All  strong  carmina- 
tives do  this  to  some  extent,  but  camphor,  valerian,  and  a  few 
other  drugs  seem  to  exert  an  antihysteric  influence  quite  out  of 
proportion  to  their  value  as  carminatives.  This  probably  is 
the  effect  of  stimulation  of  the  higher  controlling  centers  of  the 
brain  (those  governing  reason,  self-control,  will,  etc.).  That 
camphor  is  a  cerebral  stimulant  is  shown  by  increased  intel- 
lectuality and  by  the  appearance,  after  excessive  doses,  of  de- 


202  PHARMACOLOGY   AND   THERAPEUTICS 

lirium,  maniacal  excitement,  and  motor  restlessness  leading  up 
to  epileptiform  convulsions. 

Medulla. — The  slight  stimulation  of  the  respiratory  and 
vagus  centers  and  the  intermittent  stimulation  of  the  vaso- 
constrictor center  have  been  mentioned  above. 

Peripheral  Nerves. — Prolonged  application  to  the  skin  of  a 
strong  preparation,  such  as  menthol-camphor,  results  in  a  lessen- 
ing of  the  pain  sense  from  depression  of  the  ends  of  the  sensory 
nerves. 

Temperature. — The  dilatation  of  the  skin-vessels  promotes 
sweating  and  allows  more  blood  to  come  to  the  surface  of  the 
body  to  be  cooled,  so  the  drug  tends  to  lower  temperature  in 
fever  and  to  lessen  internal  congestion  (hence  its  use  internally 
in  colds) .     But  camphor  is  not  a  strong  antipyretic. 

Genito-urinary . — It  is  said  to  be  aphrodisiac,  but  there  is 
just  as  much  evidence  that  it  is  anaphrodisiac.  As  a  matter  of 
fact,  the  powerful  psychic  factors  brought  to  play  in  sexual 
manifestations  render  it  very  difficult  to  judge  of  the  effect  of  a 
drug. 

Secretions. — All  tend  to  be  slightly  increased,  the  sweat  and 
mucus  particularly.  This  is  of  too  little  degree,  however,  to  be 
of  use  in  medicine. 

Elimination. — In  the  urine,  combined  with  glycuronic  acid, 
also  in  the  sweat  and  feces,  and  perhaps  in  the  bronchial  mucus. 

Toxicology. — There  have  been  a  number  of  deaths  from  cam- 
phor. The  symptoms  are  those  of  cerebral  stimulation,  viz., 
intellectual  and  motor  activity,  great  excitement,  even  to  ma- 
niacal delirium,  and  epileptiform  convulsions.  This  stage  is 
followed  by  collapse,  coma,  and  death.  The  treatment  is 
whisky  and  bromides. 

Some  years  ago,  while  a  medical  student,  I  came  across  a  case 
of  death  in  a  child  of  two  years  from  one  teaspoonful  of  spirit  of 
camphor,  i.  e..  6  grains  (0.4  gm.).  Recently  one  of  my  female 
patients  took  a  tablespoonful  of  the  spirit  of  camphor,  i.  e.,  24 
grains  (1.6  gm.)  of  camphor,  and  became  wide  awake  and  excited 
and  had  real  intellectual  stimulation,  as  if  she  had  taken  strong 
coffee.  Motor  activity  was  not  pronounced,  but  for  several 
hours  there  was  a  sense  of  loss  of  power  in  the  legs.  The  alcohol 
present,  which  was  as  much  as  in  one  ounce  of  whisky,  possibly 
served  as  an  antidote  and  prevented  more  marked  effects.  It 
may  indeed  have  been  the  cause  of  the  sensation  of  diminished 
power  in  the  legs.  Barker  reports  the  death  of  a  female  child, 
sixteen  months  old,  after  swallowing  probably  y2  ounce  of 
camphorated  oil   (48  grains  of  camphor),  some  of  which  was 


AMMONIUM  203 

vomited.     Heard  and  Brooks  report  the  injection  of  50  grains 
(3.3  gm.)  in  oil  without  toxic  manifestations. 

Therapeutics. — Locally,  it  may  be  employed —  (1)  As  a 
counterirritant.  Camphorated  oil  is  a  very  weak  preparation, 
but  may  be  used  for  children.  It  is  rubbed  into  the  skin  in  pain 
or  inflammation  of  the  chest  and  throat,  and  in  neuralgic  and 
muscular  pains.  For  adults  the  camphorated  oil  may  be  mixed 
with  an  equal  quantity  of  the  oil  of  turpentine.  Menthol-cam- 
phor and  chloral-camphor  are  strong  liquids  which  are  employed 
in  toothache,  neuralgia,  and  muscular  and  joint  pains.  (2)  As 
a  cooling  application — the  spirit  is  applied  in  headache  and  in 
itching  and  erythema  of  the  skin.  It  acts  as  an  evaporating 
liniment.  (3)  As  a  stimulant  and  antiseptic  to  mucous  mem- 
branes in  catarrh  of  nose  and  throat.  It  may  be  added  to  oily 
sprays,  or  used  by  inhalation.  (4)  As  a  carminative  in  flatulence 
or  colic  (spirit  or  water).  (5)  .4s  anti-diarrheic  (spirit,  or  pills 
of  camphor  and  opium). 

Systemically ,  it  may  be  employed — (1)  In  colds,  to  lessen 
internal  congestion  and  fever.  (2)  As  an  antipyretic  in  fever 
mixtures  (as  camphor  water).  (3)  To  overcome  nervous  insta- 
bility and  hysteric  conditions.  (4)  As  an  emergency  circulatory 
stimulant  in  collapse  or  shock.  (5)  In  pneumonia,  Seibert 
(1913)  recommends  hypodermatic  doses  of  10  c.c.  of  a  30  per 
cent,  camphorated  oil  for  each  100  pounds  of  body  weight.  He 
repeats  the  dose  every  eight  to  twelve  hours. 

Administration. — For  carminative  or  systemic  effects,  the 
water  or  the  spirit,  the  latter  being  dropped  on  a  lump  of  sugar. 

For  diarrhea  the  preferred  preparations  are  Squibb 's  Diarrhea 
Mixture,  Sun  Cholera  Drops,  and  Camphor  and  Opium  Pills 
— camphor,  2  grains  (0.13  gm.);  opium,  1  grain  (0.06  gm.). 

As  a  circulatory  stimulant  it  is  employed  hypodermatically 
in  solution  in  alcohol,  ether,  or  oil  (camphorated  oil  is  a  20  per 
cent,  solution  in  cottonseed  oil).  These  solutions  are  irritant  to 
the  tissues. 

AMMONIUM 

The  ammonium  radicle  (NH4)  is  of  dual  nature,  for,  on  the 
one  hand,  it  is  strongly  alkaline  and  forms  salts  homologous  with 
those  of  the  alkali  metals,  K,  Na,  Li;  and,  on  the  other  hand,  it 
can  liberate  the  irritating  ammonia  gas  (NH3)  from  its  com- 
pounds. From  a  medical  point  of  view,  it  thus  forms  two  series 
of  compounds — those  whose  action  depends  upon  free  ammonia, 
and  those  which  act  as  salts  in  the  body.  Those  which  act  as 
salts  may  be  conveniently  considered  as  of  three  distinct  types, 
according  to  their  therapeutic  uses,  viz.:  (a)  the  chloride;  (b) 
the  acetate;  (c)  the  salts  in  which  the  NH4  ion  is  of  less  impor- 


204  PHARMACOLOGY   AND    THERAPEUTICS 

tance  than  the  other  ions.     We  shall  take  up  the  preparations 
according  to  this  classification. 


I.  Those  Whose  Action  Is  Dependent  Upon  Free  Ammonia 

These  include  preparations  of  the  gas  itself,  of  the  hydroxide, 
and  of  the  carbonate. 

Preparations. — i.  Stronger  water  (aqua  ammoniae  fortior), 
containing  28  per  cent,  by  weight  of  NH3  gas — not  used  inter- 
nally. 

2.  Water  (aqua  ammoniae;  spirit  of  hartshorn),  10  per  cent., 
7.5  minims  (0.5  ex.). 

3.  Spirit  (spiritus  ammoniae),  10  per  cent.,  5  minims  (0.3  c.c). 

4.  Aromatic  spirit  (spiritus  ammoniae  aromaticus),  9  per  cent, 
of  ammonia  water  and  3.4  per  cent,  of  carbonate,  with  the  aro- 
matic oils  of  lemon,  lavender  flowers,  and  nutmeg.  Dose,  30 
minims  (2  c.c). 

5.  Liniment  (35  per  cent,  of  ammonia  water  with  cottonseed 
oil),  for  external  use  only. 

6.  Ammonium  carbonate — a  mixture  of  acid  ammonium  car- 
bonate, NH4HCO3,  and  ammonium  carbamate,  NH4NH0CO2. 
It  is  wholly  soluble  in  4  parts  of  water,  but  the  carbamate  por- 
tion alone  is  soluble  in  alcohol.  It  is  decomposed  by  hot  water. 
It  can  yield  over  30  per  cent,  of  ammonia  gas,  but  it  gives  this 
off  more  slowly  than  do  the  liquid  preparations,  so  is  less  active. 

All  these  preparations  liberate  strong  ammonia  vapor,  and 
in  consequence  are  locally  irritating  and  strongly  antacid.  For 
internal  use  all  should  be  well  diluted. 

Pharmacologic  Action. — The  Skin. — Ammonia  water,  and 
much  more  so  the  stronger  water,  is  strongly  counterirritant. 
It  is  capable  of  producing  not  only  a  rubefacient  effect,  but  more 
marked  degrees  of  irritation,  as  shown  by  the  formation  of  ves- 
icles (vesicant  effect)  or  of  blisters  (epispastic  effect).  Or  it 
may  cause  destruction  of  the  tissue  (caustic  effect). 

Mucous  Membranes. — All  the  preparations  are  irritant. 
Ammonia  gas  is  extremely  irritating  to  eyes,  nose,  and  respiratory 
passages,  and  its  sudden  inhalation  may  cause  a  momentary 
cessation  of  breathing,  with  shedding  of  tears  and  great  dis- 
comfort. 

Alimentary  Tract. — The  preparations  are  irritant  to  mouth, 
throat,  and  stomach,  and  should  be  well  diluted  before  admin- 
istration. They  are  carminative  and  strongly  antacid,  and  if 
given  during  the  digestive  period,  may  neutralize  the  hydro- 
chloric acid  of  the  gastric  juice,  with  the  formation  of  ammonium 
chloride.     Being  alkaline,  they  also  tend  to  liquefy  mucus. 


AMMONIUM  205 

Absorption. — Ammonia  gas,  when  inhaled,  is  only  slightly 
absorbed,  but  the  liquid  preparations  are  rapidly  taken  up  from 
the  stomach  or  intestines,  and  unless  changed  to  chloride  by  the 
acid  in  the  stomach,  appear  in  the  portal  blood  as  the  carbonate 
or  carbamate. 

As  ammonia  is  a  regular  constituent  of  the  alimentary  prod- 
ucts, and  as  the  carotid  blood  contains  only  2  to  3  mg.  of  NH3  in 
100  c.c,  while  the  portal  blood  contains  4  to  6  mg.,  and,  during 
digestion,  even  8  mg.,  per  100  c.c,  it  is  evident  that  there  is  a 
certain  body  mechanism  for  the  disposal  of  alimentary  ammo- 
nium. It  might  be  well,  therefore,  to  ask  ourselves  what  becomes 
of  ammonia  given  by  mouth  as  medicine. 

If  ammonium  carbonate  is  administered  by  mouth  to  an 
animal,  there  is  no  increase  of  NH3  in  the  urine,  but  a  propor- 
tional increase  in  urea.  Asher  injected  the  carbonate  and  the 
tartrate  of  ammonium  into  the  portal  veins  of  fasting  dogs,  and 
found  that  the  lymph  in  the  thoracic  duct  contained  more  urea 
than  before,  the  urea  evidently  coming  from  the  liver.  Bain- 
bridge,  with  similar  experiments,  was  unable  to  confirm  Asher's 
results;  but  Weintraud,  on  administering  up  to  9  grams  of  am- 
monium carbonate  by  mouth,  found  no  increase  in  the  urinary 
excretion  of  ammonia,  but  regularly  an  increase  in  the  urinary 
urea  proportional  to  the  ammonia  administered;  and  this  was 
in  hepatic  cirrhosis,  where  the  liver  was  partly  impaired.  Then, 
too,  in  other  cases  of  hepatic  insufficiency  due  to  various  liver 
diseases  more  ammonia  and  a  proportionate  diminution  in  the 
urea  have  been  found  in  the  urine. 

If  ammonium  carbonate  is  added  to  defibrinated  blood  used 
to  perfuse  a  recently  excised  mammalian  liver,  the  urea  in  .the 
emerging  blood  is  increased  200  or  300  per  cent.,  and  ammonium 
carbonate  decreases  correspondingly  (Starling).  In  a  dog  the 
liver  may  be  experimentally  side-tracked  by  diverting  the  blood 
from  the  portal  vein  by  a  cannula  to  the  renal  vein  or  by  an  Eck 
fistula,  and  tying  the  portal  vein  to  keep  its  blood  out  of  the  liver. 
The  result  of  this  is  that  more  ammonia  and  less  urea  are  regu- 
larly found  in  the  urine,  the  urine  becomes  alkaline,  and  the 
animal  goes  into  a  state  of  vomiting,  thirst,  muscular  weakness, 
ataxia,  and  stupor,  followed  by  cerebral  excitement,  convulsions, 
coma,  and  death  in  twelve  to  twenty-four  hours.  These  are  the 
symptoms  which  result  when  ammonia  is  injected  directly  into 
the  circulation.  In  these  cases  the  carotid  blood  contains  three 
or  four  times  the  normal  amount  of  ammonia,  or  about  the  same 
proportion  as  in  the  portal  blood. 

It  is  evident,  then,  that  the  liver  is  an  important  factor  in 
the  disposal  of  ammonia,  and  that  if  the  liver  is  functionating 


206  PHARMACOLOGY  AND   THERAPEUTICS 

properly,  it  can  effectually  prevent  the  passage  of  ammonia 
from  the  alimentary  tract  to  the  systemic  circulation.  It  does 
this  by  changing  the  ammonia  to  urea,  the  changes  being  repre- 
sented by  the  following  formulae: 

i.  NH4HCO?.NH4NH2C02   =   3CO(NH2)2+C02+5H20 

Commercial  ammonium  Urea 

carbonate 

2.  NH4NH2C02  =   CO(NH2)2+H20 
Ammonium  Urea 
carbamate 

3.  (NH4)2C03       =   CO(NH2)2+2H20 

Neutral  ammon-  Urea 

ium  carbonate 

It  becomes  a  question,  then,  whether  any  of  the  ammonium 
hydroxide  or  carbonate  administered  by  mouth  gets  through  the 
liver  without  being  changed  to  urea.  If  all  the  ammonia  is 
changed,  then  no  ammonia  gets  into  the  circulation  to  exert  a 
systemic  action,  and  the  only  effects  of  these  ammonia  prepara- 
tions taken  by  mouth  must  be  the  local  and  reflex  ones.  It  is 
possible,  of  course,  that  some  of  the  ammonia  gets  through  the 
liver  without  change,  or  passes  into  the  circulation  by  way  of 
the  lymphatics  without  immediately  entering  the  liver,  and  so 
exerts  its  systemic  effects  before  it  is  changed  to  urea.  If  any 
escapes  the  liver,  it  is  probably  changed  to  urea  by  the  muscles. 
It  is  probable  that  some  of  it  is  absorbed  as  ammonium  chloride, 
which  it  forms  with  the  hydrochloric  acid  of  the  gastric  juice. 

Ammonium  carbonate  administered  hypodermatically  es- 
capes the  liver  for  a  time,  and  exerts  a  strong  systemic  poisonous 
action;  but  even  when  it  is  administered  in  this  way,  it  is  soon 
changed  to  urea  by  the  muscles  and  liver. 

Nervous  System. — Following  the  inhalation  of  the  gas  or  the 
swallowing  of  the  preparations,  there  is  an  immediate  reflex  stimu- 
lation of  the  vasoconstrictor  and  respiratory  centers  in  the 
medulla,  and  perhaps  of  the  vagus  or  the  accelerator  centers. 
This  effect  is  evidently  reflex,  from  the  surface  irritation;  for  it 
is  almost  instantaneous,  and  manifests  itself  before  the  drug  can 
be  absorbed.  This  prompt,  though  ephemeral,  reflex  stimulation 
is  taken  advantage  of  to  relieve  mild  collapse,  as  in  fainting  or 
feelings  of  faintness.  If  the  drug  is  absorbed  into  the  systemic 
blood-stream,  as  when  administered  intravenously,  and  perhaps 
when  given  hypodermatically,  there  is  a  direct  stimulation  of 
the  vagus  and  vasoconstrictor  centers.  There  is  also  increased 
irritability  of  brain  and  cord,  so  that  after  large  doses  there  may 
be  convulsions  like  those  from  strychnine,  followed  by  coma  and 
death. 


AMMONIUM  207 

Circulatory  Organs. — The  immediate  result  of  the  reflex 
effect  upon  the  vagus,  vasoconstrictor,  and  accelerator  centers 
is  a  rise  in  arterial  pressure,  though  the  rate  of  the  heart  is  vari- 
able, according  as  vagus  stimulation  predominates,  or  accelera- 
tor. After  absorption,  as  from  hypodermic  dosage,  there  is 
slight  direct  stimulation  of  the  vasoconstrictor  and  the  vagus 
centers  and  of  the  heart  muscle,  so  that  arterial  pressure  is 
raised;  but,  owing  to  the  rapid  change  of  the  drug  in  the  system, 
this  is  of  short  duration.  Very  large  doses  depress  the  heart 
muscle  at  once,  or  after  a  brief  period  of  stimulation. 

The  whole  action  is  so  brief  that  ammonia,  whether  inhaled 
or  given  by  mouth  or  hypodermatically,  is  of  use  as  a  circulatory 
stimulant  only  momentarily,  and  it  has  its  great  value  in  just 
those  passing  depressions  of  the  circulation  which  show  in  feel- 
ings of  faintness  or  fainting. 

Respiratory  System. — A  strong  inhalation,  or  a  concentrated 
dose  by  mouth,  will  stop  the  respiration  for  a  moment;  and  this 
is  followed  by  a  reflex  stimulation  of  the  respiratory  center  from 
the  local  irritation.  If  the  drug  is  absorbed,  there  is  a  direct 
stimulation  of  the  center.     So,  in  any  case,  breathing  is  deepened. 

When  taken  by  mouth,  the  bronchial,  nasal,  and  throat 
mucus  are  believed  to  be  rendered  more  fluid,  and  for  this  reason 
the  carbonate  is  used  in  cough  mixtures.  But,  as  noted  above, 
the  carbonate  is  in  all  probability  changed  either  to  the  chloride 
or  to  urea,  hence  it  does  not  act  by  its  alkaline  property  to  fluidify 
the  mucus.  In  addition,  ammonia  is  not  excreted  by  the  lungs 
(Magnus)  or  in  the  bronchial  mucus,  for  after  the  administration 
it  has  been  found  neither  in  the  bronchial  mucus  nor  in  the  ex- 
pired air  (Mayr).  The  probability  is  that  it  acts  reflexly  from 
the  throat  or  stomach  by  a  nauseant  action  to  increase  and 
fluidify  the  bronchial  secretions.  In  those  cases  in  which  it  is 
changed  to  the  chloride  it  may  stimulate  the  bronchial  glands  or 
the  secretory  nerve-endings  or  centers,  though  we  have  no  proof 
of  this.     (See  Expectorants.) 

Secretions. — As  just  stated,  it  tends  to  loosen  and  fluidify 
mucus.  This  effect  is  especially  to  be  noted  in  the  nose,  throat, 
bronchi,  and  stomach.  Both  urea  and  ammonium  chloride  are 
diuretic. 

Elimination. — The  carbonate  and  hydroxide  are  changed 
to  the  chloride  or  to  urea.  In  the  latter  case  the  excretion  of 
urea  is  increased  without  increase  in  general  metabolism.  The 
blood  is  not  rendered  more  alkaline,  as  it  is  by  the  hydroxides 
and  carbonates  of  the  fixed  alkalies,  and  the  urine  reaction  is 
probably  unaffected. 

Toxicology. — 1.  From  Swallowing. — Ammonia  water,   swal- 


208  PHARMACOLOGY  AND  THERAPEUTICS 

lowed  undiluted,  causes  great  local  irritation  and  inflammation 
of  mouth,  throat,  esophagus,  and  stomach.  There  may  be  vomit- 
ing. The  inflammation  may  go  on  to  ulceration  or  general 
sloughing;  and,  if  the  patient  recovers,  may  leave  cicatricial 
constrictions  which  will  give  trouble  in  after-life.  If  the  burns 
are  very  extensive,  death  may  result  from  shock.  The  ammonia 
fumes  may  get  into  the  larynx  and  produce  edema  of  the  glottis. 
Treatment:  In  the  mouth  or  stomach,  the  poison  may  be  neu- 
tralized by  mild  acids,  such  as  vinegar  or  lemon-juice;  the  pain 
and  inflammation  may  be  lessened  by  bland  oils  or  fats,  such  as 
olive  or  linseed  oil,  lard  or  butter,  or  by  the  white  of  egg,  milk, 
or  demulcent  mucilaginous  drinks. 

2.  From  Inhalation. — Strong  ammonia  fumes  inhaled,  as 
from  the  escape  of  the  gas  in  ice-plants,  or  when  the  liquid  is 
swallowed,  may  cause  swelling  and  inflammation  of  the  larynx 
and  bronchi,  and  through  edema  or  spasm  of  the  glottis  may 
cause  asphyxia  and  death.  The  treatment  is  to  give  plenty  of 
air  or  inhalations  of  oxygen.  If  the  glottis  is  closed  so  as  to 
prevent  breathing,  intubation  or  tracheotomy  should  be  per- 
formed. If  there  is  edema  of  the  glottis,  the  tissues  should  be 
cut  at  once  to  relieve  the  swelling. 

Effects  After  Absorption. — If  the  poison  is  absorbed,  there  may 
be  strychnine-like  convulsions,  collapse,  coma,  and  asphyxia, 
death  being  due  to  paralysis  of  the  respiratory  center  or  to  the 
convulsive  interference  with  breathing.  The  treatment  is 
artificial  respiration,  oxygen,  absolute  repose,  external  heat,  and 
other  treatment  for  collapse. 

Therapeutics  and  Administration. — i.  As  a  counterirritant— 
ammonia  liniment  or  ammonia  water.  As  a  blistering-agent  to 
the  gums — ammonia  water. 

2.  As  a  rapid  reflex  circulatory  and  respiratory  stimulant  in 
fainting  or  feelings  of  faintness — ammonia  gas  inhaled  from 
ammonia  water  or  smelling  salts;  or  the  aromatic  spirit  of  am- 
monia, taken  by  mouth.  Smelling  salts  are  mostly  made  of 
cakes  of  ammonium  carbonate  covered  with  the  spirit  of  ammonia 
containing  aromatic  oils,  such  as  the  oil  of  lavender. 

3.  As  an  antacid  carminative  in  digestive  disturbances  and 
headache,  and  as  a  morning  "pick-me-up"  after  a  debauch — 
the  aromatic  spirit. 

4.  As  an  expectorant  to  fluidify  thick  and  tenacious  mucus 
of  the  respiratory  tract — the  carbonate. 

Contraindication. — Urea  retention,  as  in  nephritis  and 
uremia. 


AMMONIUM  209 

II.    The  Ammonium  Compounds  Which  Are  Not  Depen- 
dent for  Their  Activity  on  Their  Liberation  of  NH3 

1.  Ammonium  Chloride 

The  chloride  or  muriate  of  ammonia  or  sal  ammoniac  (NH4CI) 
has  a  sharply  salty  taste,  and  is  soluble  in  2  parts  of  water  and 
50  of  alcohol.  Dose,  8  grains  (0.5  gm.).  The  only  official 
preparation  is  the  troche  (trochiscus  ammonii  chloridi),  which 
contains  i>£  grains  (0.9  gm.)  of  ammonium  chloride  with 
sugar,  licorice,  etc. 

Pharmacologic  Action. — The  chloride  liberates  ammonia  very 
slowly  indeed,  and  is  neither  antacid  nor  caustic. 

Local  Action. — It  has  a  marked  salt  action,  i.  e.,  in  strong 
solution  shrinks  the  tissues  by  abstracting  water,  and  is  irritant. 
In  proper  dilution  it  is  only  slightly  irritant. 

In  the  mouth  it  is  irritant  and  astringent,  causing  shrinkage 
of  the  membranes;  but  in  response  to  the  irritation  there  is  a 
prompt  reflex  flow  of  saliva,  which  serves  as  a  diluent  and  moistens 
the  mouth.     In  the  stomach,  it  is  also  irritant  unless  well  diluted. 

Absorption. — The  chloride  is  rapidly  absorbed  from  the 
stomach  and  is  not  converted  to  urea  in  the  liver  (Bainbridge). 
(The  sulphate,  in  which  the  ammonium  ion  is  combined  with 
the  non-penetrating  sulphate  ion,  is  not  readily  absorbed  and  is 
consequently  laxative,  but  it  is  not  employed  in  medicine.) 

Its  systemic  action  is  essentially,  if  anything,  to  increase 
secretions,  and  it  has  the  reputation  of  increasing  and  fluidifying 
the  mucous  secretions  of  nose,  throat,  and  bronchi.  Ammonia 
is  not  found  either  in  the  excreted  mucus  or  in  the  expired  air, 
therefore  any  action  on  the  bronchi  is  not  a  remote  local  one,  and, 
if  it  really  exists,  is  probably  a  stimulation  of  the  secretory  ner- 
vous mechanisms.  This  may  be  a  result  of  a  nauseant  action. 
(See  Expectorants.)  By  its  action  as  a  salt  it  may  slightly  increase 
the  other  secretions,  especially  the  saliva,  the  sweat,  and  the 
urine.     It  is  not  a  circulatory  stimulant,  either  reflex  or  direct. 

Excretion. — Traces  have  been  found  in  several  secretions, 
but  almost  all  of  it  is  excreted  as  ammonium  chloride  in  the 
urine,  the  reaction  of  the  urine  and  the  amount  of  urea  being 
practically  unchanged.  It  has  been  calculated  that  the  chloride 
ingested  is  broken  up  in  the  liver  or  in  other  parts  of  the  body 
with  the  liberation  of  hydrochloric  acid  and  the  formation  of 
urea,  the  HC1  thus  set  free  being  immediately  neutralized  and 
changed  back  to  ammonium  chloride  by  NH3  manufactured  by 
the  body-cells;  and  that  it  is  this  freshly  manufactured  chloride 
that  is  excreted.  This  may  be  true,  but  in  any  case,  as  suggested 
by  the  work  of  Bainbridge  on  the  lymph  of  the  thoracic  duct, 
14 


2IO  PHARMACOLOGY  AND    THERAPEUTICS 

what  leaves  the  liver  is  the  chloride,  and  ammonia  poisoning 
does  not  result. 

Therapeutics. — For  acute  pharyngitis  the  troches  or  tablets 
may  be  dissolved  in  the  mouth — a  favorite  remedy  of  the  laity. 
Thus  employed,  the  chloride  is  at  first  stimulating  and  astringent, 
so  that  it  causes  a  drawing-up  of  the  relaxed  mucous  membrane, 
with  removal  of  its  edematous  state;  it  also  promotes  the  flow  of 
saliva,  so  may  relieve  congestion  and  dryness  of  the  throat.  In 
laryngitis  or  bronchitis  the  drug  is  occasionally  inhaled  as  vapor, 
the  vapor  being  formed  at  the  moment  required  by  the  admixture 
of  ammonia  and  hydrochloric  acid  gases  in  a  special  apparatus. 
But  its  most  frequent  employment  is  in  cough  mixtures,  to  in- 
crease the  flow  of  mucus  in  the  dry  stages  of  nasal,  throat,  and 
bronchial  inflammations,  i.  e.,  when  the  congestion  is  great 
without  mucous  flow,  or  when  the  mucus  is  thick  and  tenacious. 

2.  Ammonium  Acetate 

The  acetate,  NH4C2H3O2,  is  an  unstable  salt,  and  on  this 
account  is  prepared  in  solution  when  required.  There  are  two 
official  preparations — the  solution  of  ammonium  acetate  (liquor 
ammonii  acetatis;  spirit  of  Mindererus),  and  the  solution  of 
iron  and  ammonium  acetate  (liquor  ferri  et  ammonii  acetatis; 
Basham's  mixture),  the  dose  of  each  of  which  is  2  drams  (8  c.c). 
The  solution  of  ammonium  acetate  should  be  freshly  prepared,  and 
should  contain  CO>  gas.  It  is  a  palatable,  slightly  salty  prepara- 
tion, is  quickly  absorbed,  and  is  changed  to  urea  in  the  liver,  the 
urea  promoting  the  flow  of  urine.  It  may  also  have  a  tendency 
to  increase  the  sweat.  It  is  employed  as  a  refreshing  but  weakly 
acting  diaphoretic  and  diuretic  in  fevers,  especially  those  of 
children.  Basham's  mixture  is  a  palatable  iron  preparation.  As 
it  contains  free  acid,  it  should  be  administered  well  diluted  and 
through  a  tube,  to  protect  the  teeth.  It  is  employed  in  anemic 
conditions  for  its  iron,  and  in  functional  albuminuria  or  chronic 
nephritis  for  both  its  iron  and  its  ammonium  acetate. 

3.  The  other  official  salts  of  ammonium  are  the  bromide, 
iodide,  benzoate,  salicylate,  and  valerate.  In  these  the  effect 
of  the  ammonium  radicle  is  overshadowed  by  the  relatively  more 
potent  acid  radicle,  so  that  these  salts,  except  in  large  doses, 
have  practically  the  action  of  the  potassium  and  sodium  salts  of 
the  same  acids.  They  belong,  pharmacologically,  with  the 
groups  of  bromides,  iodides,  salicylates,  etc. 

Mechanical  Measures  for  Raising  Arterial  Pressure 

In  hemorrhage  or  collapse,  the  immediate  indication  is  to 
restore  the  circulation  of  the  brain  centers,  particularly  of  the 


TO   INCREASE   THE   BLOOD   IN   THE   ARTERIES  211 

vasoconstrictor  and  respiratory;  so  mechanical  measures,  to 
increase  the  blood  of  the  trunk,  such  as  raising  the  feet  and 
lowering  the  head,  or  tightly  bandaging  the  limbs,  toes,  or 
ringers  upward,  are  valuable  measures.  By  this  latter  method 
the  blood-pressure  may  sometimes  be  raised  30  or  40  millimeters 
of  mercury,  and  the  bandages  may  be  kept  on  for  half  an  hour 
without  harm  to  the  limbs. 

For  use  in  shock  Crile  has  devised  a  pneumatic  suit,  by  which 
the  surface  pressure  on  the  body  may  be  increased  or  reduced  at 
will.  By  it  he  has  raised  the  arterial  pressure  as  much  as  75  mm., 
and  maintained  the  rise  for  some  time.  To  accomplish  the  same 
purpose,  Meltzer  recommends  bandaging  the  abdomen  and  plac- 
ing weights  upon  it. 

MEASURES  FOR  INCREASING   THE  VOLUME   OF  THE  BLOOD   IN 

THE  ARTERIES 

These  are — (1)  The  transfusion  of  blood;  and  (2)  the  admin- 
istration of  saline  solution  (by  intravenous  infusion,  by  hypo- 
dermoclysis,  or  by  rectal  injection). 

Transfusion  is  the  transmission  of  blood  from  an  artery  of 
one  person  to  the  vein  or  artery  of  another.  It  requires  careful 
technic,  involves  the  willingness  of  a  second  person  to  contribute 
blood,  and  is  not  free  from  danger.  The  dangers  are — (1) 
Clotting  (2)  the  transmission  of  disease,  such  as  syphilis,  (3)  the 
collapse  of  the  donor  of  the  blood,  and  (4)  hemolysis.  Before 
transfusion  the  blood  of  the  donor  should  be  tested  with  that  of 
the  patient  for  fear  of  hemolysis.  This  is  especially  likely  to  occur 
in  infants  or  in  the  presence  of  a  malignant  tumor  (Crile).  By 
recent  improved  methods  the  clotting  and  technical  difficulties 
have  been  much  reduced,  so  that  transfusion,  which  was  at  one 
time  abandoned,  has  again  come  into  general  use.  The  artery 
of  the  donor  is  usually  connected  with  a  vein  of  the  recipient  by 
some  apparatus,  and  the  blood  allowed  to  flow  gently  for  fifteen 
or  twenty  minutes,  or  until  the  donor  begins  to  show  the  effects 
of  loss  of  blood.  In  some  cases  transfusion  into  an  artery  brings 
a  more  prompt  response  than  into  a  vein.  For  in  transfusion 
into  a  vein  the  transfused  blood  may  merely  increase  the  volume 
of  the  already  excessive  venous  blood,  and  in  any  case  must  pass 
to  the  right  heart  and  through  the  pulmonary  circulation  before 
the  left  heart  can  act  upon  it ;  while  by  transfusion  into  an 
artery  the  new  blood,  owing  to  the  increased  peripheral  resist- 
ance, stimulates  the  heart  and  invigorates  the  coronary  circula- 
tion. 

Transfusion  of  blood  has  advantages  over  saline  infusion, 
for  the  new  blood  supplies  nutritive  material,  oxyhemoglobin, 


212  PHARMACOLOGY  AND  THERAPEUTICS 

and  carbon  dioxide,  the  latter  tending  to  overcome  acapnia  in 
shock.  The  added  liquid  is  not  so  quickly  transuded  out  or 
excreted  as  a  salt  solution  would  be;  consequently  it  tends  to 
maintain  the  increased  arterial  pressure  for  a  longer  time.  In 
hemorrhage  transfusion  may  result  in  increased  coagulability  of 
the  blood. 

Levin  has  made  a  comparative  study  of  the  ability  of  saline 
solutions  and  transfused  blood  to  replace  blood  lost  by  hemor- 
rhage. In  a  number  of  dogs  he  let  out  enough  blood  to  kill,  i.  e., 
about  4.5  to  5.5  per  cent,  of  the  body  weight,  and  allowed  the 
heart  to  come  to  a  standstill.  On  replacing  the  blood  with  saline 
the  heart  began  to  beat  again  for  a  time,  but  the  animal  did  not 
revive.  On  replacing  the  lost  blood  with  fresh  blood  by  trans- 
fusion, the  heart  began  to  beat  again,  and  usually  in  as  little  as 
five  minutes  this  resulted  in  the  dog's  return  to  just  as  good 
condition  as  before  the  experiment. 

Therapeutics. — 1.  Collapse  or  shock  from  any  cause,  but 
especially  when  there  is  hemorrhage. 

2.  Poisoning  by  carbon  monoxide  (illuminating  gas) — after 
removal  of  a  portion  of  the  blood  of  the  patient  by  venesection. 

3.  Profound  malnutrition. 

4.  Profound  anemia  of  secondary  type  or  from  hemorrhage. 
In  primary  pernicious  anemia  and  leukemia  the  effect  of  the 
new  blood  is  very  short  lived. 

5.  Protracted  weakness  or  prostration. 

(Defibrinated  blood  was  formerly  employed  in  some  instances, 
but  the  process  of  defibrination  introduces  possibilities  of  infec- 
tion and  is  decidedly  disadvantageous.) 

Saline  Infusion. — Intravenous  infusion  requires  a  graduated 
reservoir  for  the  saline,  a  rubber  tube  for  transmission  of  the 
liquid,  and  a  cannula  or  nozzle  (the  glass  portion  of  an  eye 
dropper  will  do)  for  insertion  into  the  vein.  A  tourniquet  is 
placed  on  the  upper  arm,  and  a  fair-sized  vein,  the  median  basilic, 
for  example,  is  exposed  and  freed  from  the  surrounding  tissues 
by  blunt  dissection.  Around  it  is  passed  a  double  ligature,  of 
which  the  distal  loop  is  tied  tightly  and  the  proximal  portion  is 
slipped  up  the  vein  out  of  the  way.  The  empty  vein  (proximal 
to  the  tied  ligature)  is  then  snipped  on  one  side  with  a  pair  of 
scissors  or  slit  with  a  scalpel.  The  sterilized  saline  solution,  at  a 
temperature  of  uo°  to  1150  F.,  is  placed  in  the  reservoir  some 
three  or  four  feet  above  the  vein,  and  is  allowed  to  run  through 
the  tube  and  cannula.  When  all  air-bubbles  have  passed  out, 
its  stream  is  directed  against  the  slit  in  the  vein  to  force  the  slit 
open.  The  end  of  the  cannula  is  then  easily  passed  through  the 
slit  into  the  vein,  and  is  tied  there  with  the  upper  ligature.     The 


TO   INCREASE    THE   BLOOD    IN    THE    ARTERIES  213 

tourniquet  is  removed  and  the  saline  allowed  to  pass  into  the 
vein  at  a  steady  rate  in  the  direction  toward  the  heart,  until 
the  desired  quantity  has  been  administered.  The  cannula  is 
then  removed  and  the  vein  tied  off.  The  amount  administered 
is  from  500  to  1500  c.c.  (about  1  tq  3  pints),  quantities  much 
above  this  being  contraindicated,  as  noted  below. 
The  solutions  employed  for  infusion  are: 

1.  Normal  saline — which  contains  0.9  per  cent,  of  sodium 
chloride,  about  a  full  teaspoon  to  one  pint  (for  frogs,  normal 
saline  is  of  0.7  per  cent,  strength).  This  is  the  most  universally 
employed  infusion  fluid;  but,  because  of  the  absence  of  all  other 
salts,  especially  those  of  potassium  and  calcium,  which  are 
required  by  the  tissues  and,  according  to  Jacques  Loeb,  prevent 
sodium  chloride  poisoning,  and  because  its  reaction  is  not  alka- 
line, it  is  not  by  any  means  the  best  solution.  Indeed,  normal 
saline  is  better  made  from  hard  drinking-water,  which  contains 
calcium,  than  from  distilled  water.  For  pure  sodium  chloride 
intravenously  is  poisonous,  and  normal  saline  made  from  dis- 
tilled water  may  have  a  veratrine  action  upon  muscle,  i.  e.,  it 
may  cause  increased  contraction  with  retarded  relaxation;  while 
if  the  slightest  amount  of  a  calcium  salt  is  present,  the  chance  of 
this  action  is  avoided.  Ordinary  table  salt  regularly  contains 
some  calcium.  The  0.7  per  cent,  saline  is  not  to  be  employed, 
for  in  some  hemolytic  conditions  the  blood  has  been  found  to 
hemolize  with  this  strength  saline. 

2.  Dawson's  solution — 0.8  per  cent,  of  sodium  chloride  with 
0.5  per  cent,  of  sodium  bicarbonate. 

3.  Locke's  solution — the  best  of  all.  Its  formula  is:  Sodium 
chloride,  0.9  gm.;  potassium  chloride,  0.042  gm. ;  calcium  chloride, 
0.024  gm.;  sodium  bicarbonate,  0.03  gm.;  dextrose,  0.1  gm.;  and 
distilled  water,  a  sufficient  quantity  to  make  100  c.c.  This 
contains  the  necessary  salts,  and  is  alkaline  and  nutritive. 

4.  The  Ringer-Locke  solution — Locke's,  with  the  dextrose 
omitted. 

5.  Ringer's  solution,  much  used  in  the  laboratory,  contains 
the  chloride  of  sodium,  0.7  per  cent.,  with  the  chlorides  of  potas- 
sium and  calcium.  It  was  especially  designed  for  frogs  and 
turtles. 

To  understand  the  effects  of  saline  solutions  in  the  body,  we 
must  know  what  is  meant  by  the  physiologic  terms  filtration, 
diffusion,  and  osmosis,  and  the  nature  of  hypotonic  (hypoiso tonic) , 
isotonic,  and  hypertonic  (hyperisotonic)  solutions.  These  are 
well  explained  in  any  modern  physiology,  such  as  Schafer,  Star- 
ling, or  Howell. 

In  infusion,  a  large  quantity  of  liquid  is  passed  into  the  circu- 


214  PHARMACOLOGY  AND   THERAPEUTICS 

lation;  it  should,  therefore,  be  practically  isotonic  with  the  blood. 
If  a  hypertonic  liquid  is  employed,  i.  e.,  a  liquid  containing  too 
large  a  proportion  of  salts,  the  blood  abstracts  water  from  the 
tissues  and  swells  in  volume,  to  become  still  more  dilute  than 
the  amount  of  injected  liquid  alone  would  make  it;  a  greatly 
hypertonic  liquid  will  injure  the  blood-cells.  On  the  other  hand, 
a  hypotonic  liquid  will  tend  to  lake  the  blood;  outside  the  body,  a 
solution  of  0.4  to  0.44  per  cent,  of  sodium  chloride  will  do  this 
normally. 

The  effects  of  a  saline  infusion  differ  according  to  whether 
the  volume  of  blood  has  been  previously  decreased  or  not ;  there- 
fore must  be  considered  from  these  two  points  of  view. 

1.  When  the  Volume  of  the  Blood  has  not  been  Decreased  by 
Hemorrhage  or  Other  Cause. — -In  normal  animals  the  tendency  of 
the  blood  to  regain  its  normal  condition  is  so  pronounced  that 
almost  as  soon  as  an  infusion  is  begun  the  mechanisms  for  regula- 
tion are  started.  As  the  result  of  increased  pressure  in  the  capil- 
laries there  is  an  immediate  outpouring  of  weak  lymph,  and  this 
is  followed  by  elimination  of  liquid  through  the  intestines  and 
kidneys  (Starling),  so  that  in  half  an  hour  not  only  will  the  vol- 
ume of  the  blood  have  returned  to  normal,  but  its  constituents 
will  have  regained  their  proper  relative  proportions  (Crile). 

In  experimenting  with  saline  infusions  in  61  normal  dogs, 
Crile  found  that,  besides  the  rapid  transudation  of  lymph,  there 
was  a  dilatation  of  the  splanchnic  arterioles,  so  that  most  of  the 
extra  volume  of  blood  was  received  in  the  splanchnic  area  with- 
out raising  the  general  arterial  pressure;  thence  it  was  rapidly 
excreted  by  the  kidneys  and  intestines.  Both  on  account  of 
this  sensitive  vasomotor  mechanism  and  of  the  active  capillary 
transudation,  he  was  unable  to  get  a  rise  in  the  arterial  pressure 
of  more  than  8  mm.  of  mercury,  even  from  enormous  amounts  of 
saline.  Indeed,  the  mechanisms  for  keeping  the  blood  normal 
proved  so  active  that  after  a  certain  dilution  of  the  blood  was 
reached  it  was  practically  impossible  to  bring  about  further 
dilution,  and  the  only  result  of  further  infusion  was  to  produce 
general  edema.  The  limit  of  safe  dosage  he  ascertained  to  be 
30  c.c.  of  saline  per  kilo  of  body- weight,  which  in  the  same  ratio 
would  be  about  2200  c.c.  for  a  160-pound  man.  Clinical  experi- 
ence favors  smaller  amounts  for  man,  and  has  proved  the  danger 
of  such  large  quantities. 

So  when  the  volume  of  blood  is  already  normal,  the  addition 
of  saline  solution  has  only  a  transitory  mild  effect  on  arterial 
pressure,  and  chiefly  increases  urination  and  the  tendency  to 
edema.     It  tends  also  to  lessen  the  viscosity  of  the  blood,  but 


TO  INCREASE  THE  BLOOD  IN  THE  ARTERIES       21 5 

this  action  is  so  ephemeral  that  it  probably  has  very  little  influ- 
ence on  the  blood-stream. 

Crile  found,  further,  that  the  dilution  of  the  blood  does  not 
prevent  the  action  of  circulatory  stimulants;  that  if  vasocon- 
strictor stimulants  were  administered  at  the  same  time  as  the 
saline,  the  arterial  pressure  could  be  raised  above  normal  for  a 
time;  but  that,  when  the  splanchnic  arteries  were  excluded,  the 
dilution  of  the  blood  increased  so  rapidly  with  the  progress  of  the 
infusion  that  edema  set  in  very  quickly,  even  though  the  arterial 
pressure  was  not  essentially  raised.  This  indicates  that  if,  by 
a  strong  vasoconstrictor,  such  as  epinephrine,  dilatation  of  the 
splanchnic  arteries  is  prevented,  the  chances  of  edema  are  in- 
creased. Hence  in  intravenous  infusion,  since  the  liquid  must 
pass  to  the  right  heart  and  to  the  lungs  first,  pulmonary  edema  is 
favored;  and  especially  is  this  the  case  if  at  the  same  time  there 
is  marked  back  pressure  on  the  left  heart  from  constriction  of 
the  peripheral  arterioles.  Therefore,  as  might  be  expected,  pul- 
monary edema  is  especially  readily  brought  about  by  a  combina- 
tion of  saline  infusion  and  epinephrine. 

Summary. — When  the  volume  of  the  blood  has  not  been 
reduced,  saline  infusion  to  raise  arterial  pressure  is  almost  useless, 
and  by  producing  edema,  may  have  serious  consequences.  If 
used  as  a  medium  for  the  administration  of  drugs,  it  should  be 
employed  in  small  quantity,  and  slowly  introduced.  By  trans- 
fusion of  blood,  on  the  contrary,  it  has  been  found  possible  to 
raise  arterial  pressure  away  above  the  normal,  and  to  maintain 
it  there  for  some  little  time. 

When  the  Volume  of  the  Blood  is  Notably  Below  Normal,  as 
After  a  Large  Hemorrhage. — From  25  to  50  per  cent,  of  an  animal's 
blood  may  be  removed  and  replaced  with  saline  without  serious 
results  (Levin) .  Crile  noted  that  after  a  moderate  hemorrhage 
a  saline  infusion  would  increase  the  volume  of  the  blood  so  that 
normal  arterial  pressure  would  be  maintained  for  a  considerable 
period.  He  found  also  that  the  blood  has  a  shorter  coagulation 
time,  the  saline  thus  favoring  the  cessation  of  the  hemorrhage. 
So  saline  infusions  are  valuable  to  replace  lost  blood,  and  may  be 
used  with  advantage  whether  the  bleeding  has  stopped  or  not. 

A  few  further  observations  of  Crile  on  the  effects  of  infusions 
are  worth  mentioning:  The  temperature  of  the  infusion,  if  within 
reasonable  limits,  makes  almost  no  difference,  either  in  the  tem- 
perature of  the  patient  or  in  the  heart-beat.  The  rate  of  flow 
makes  no  difference  in  the  extent  of  the  effect  on  arterial  pressure. 
The  effect  on  respiration  is  an  increase  in  frequency  and  depth; 
but  "  from  greater  than  safe   amounts  the  breathing  becomes 


2l6  PHARMACOLOGY   AND   THERAPEUTICS 

slowed,  and  there  regularly  ensue  edema  of  the  lungs  and  death 
from  respiratory  failure." 

Therapeutics. -^-i.  In  hemorrhage — to  restore  the  blood  vol- 
ume to  normal  and  thus  permit  the  maintenance  of  arterial 
pressure.  If  the  hemorrhage  is  still  in  progress,  the  infusion 
may  check  it  by  increasing  the  coagulability  of  the  blood  (as  in 
the  hemorrhages  from  injury,  or  following  operation,  or  from 
typhoid  ulcers,  etc.).  Oxygen  may  be  first  passed  through  the 
fluid,  for  if  the  saline  is  saturated  with  oxygen,  it  favors  the 
transference  of  oxygen  to  the  tissues  at  the  capillaries. 

2.  In  cholera — to  restore  the  volume  of  the  blood  and  supply 
liquid  to  the  tissues.  The  effect  is  usually  too  short-lived, 
however. 

3.  In  toxemic  conditions — to  promote  kidney  activity,  with 
the  idea  of  carrying  out  the  poison.  In  uremia,  saline  infusion  is 
sometimes  employed  after  considerable  blood-letting,  though 
ordinarily  in  kidney  cases  the  saline  is  given  by  rectum  instead  of 
intravenously.  Levin  considered  bleeding  followed  by  infusion 
a  useless  procedure  in  toxemic  conditions,  for  he  could  obtain  no 
appreciable  effect  from  it  in  artificially  produced  toxemias.  In 
nephritis  with  edema,  salt  retention  contraindicates  the  use  of 
saline.  In  strychnine  poisoning  Delbert  has  prevented  toxic 
symptoms  by  the  use  of  saline  infusion. 

4.  In  severe  collapse  or  shock — a  small  saline  infusion  of 
about  500  c.c,  given  slowly  and  containing  adrenaline,  may  pro- 
mote the  maintenance  of  blood-pressure.  A  large  infusion,  or  an 
infusion  with  much  adrenaline,  merely  favors  the  production  of 
edema.  In  post-operative  collapse,  the  saline  may  replace  blood 
lost  in  the  operation,  but  care  must  be  used  not  to  administer 
too  great  a  quantity. 

Saline  by  Hypodermoclysis  and  Enema. — In  cases  of  col- 
lapse after  hemorrhage,  and  when  it  is  desired  to  promote  kidney 
activity,  the  saline  may  be  administered  by  rectal  enema  or  by 
hypodermoclysis.  After  hemorrhage,  absorption  from  the  rec- 
tum is  especially  rapid,  and  one  or  two  quarts  may  be  given 
by  enema  without  expulsion.  Under  ordinary  conditions,  too, 
hot  saline  by  rectum  regularly  shows  a  prompt  effect  upon  the 
kidneys.  Even  by  hypodermoclysis  over  the  abdomen,  in  the 
axillary  line,  or  beneath  the  breasts,  as  much  as  a  pint  of 
saline  may  be  used  in  some  cases  in  about  ten  or  fifteen  minutes. 

Contraindications — any  form  of  edema,  but  especially  that 
of  the  lungs,  and  that  resulting  from  sodium  chloride  retention, 
as  in  nephritis. 

Toxicology. — Chills  have  been  reported  following  saline  infu- 
sions.    Several  cases  of  death  have  occurred  from  the  use,  by 


ACONITE  217 

rectum   or   intravenously,   of   concentrated   stock   solutions   of 
sodium  chloride  in  mistake  for  normal  saline.     (See  Alkalies.) 

Remedies  Which  Lower  Blood-pressure 

These  we  are  able  to  divide  into  three  classes : 

(a)  Cardiac  depressants. 

(b)  Arterial  dilators. 

(c)  Measures  for  decreasing  the  volume  of  blood. 

The  Cardiac  Depressants 
aconite 

Aconitum  (aconite,  monkshood)  is  the  dried  tuberous  root  of 
Aconitum  napellus  (Fam.  Ranunculaccce) ,  collected  in  autumn, 
and  yielding  when  assayed  not  less  than  0.5  per  cent,  of  aconitine. 
It  is  a  European  herb,  extensively  cultivated  as  a  garden  flower. 

Constituents. — Several  alkaloids,  of  which  aconitine  is  the 
essential  active  one.  Aconine,  present  in  minute  quantity,  is 
said  to  be  a  cardiac  stimulant,  while  benzaconine,  picraconitine, 
and  aconitic  acid  are  inert. 

Preparations  and  Doses. — The  preparations  on  the  market 
are  exceedingly  variable,   many  of   them   having   been  found 
almost  inert.     They  deteriorate  rapidly  on  keeping. 
Aconite,  assaying  not  less  than  0.5  per  cent,  aconitine,  1  grain 

(0.06  gm.). 
Fluidex tract,  1  minim  (0.06  c.c). 
Tincture,  10  per  cent.,  10  minims  (0.06  c.c). 
Aconitine,  dose,  4-^  grain  (0.15  mg.),  is  insoluble  in  water 
and  soluble  in  oil  or  alcohol.     It  is  one  of  the  most  powerful 
poisons  known.     As  marketed,  it  is  highly  variable,  some 
specimens  having  been  found  a  hundred  times  as  strong  as 
others. 
Pharmacologic    Action. — Skin. — Following    the    application 
to  the  skin  of  an  oily  or  alcoholic  solution  of  aconite  there  are 
tingling,  pricking,  and  smarting  of  the  part.     This  is  not  accom- 
panied by  the   phenomena  of   counterirritation,   i.  e.,  general 
irritation  of  the  tissues,  with  redness  and  warmth,  as  after  am- 
monia or  mustard,  for  aconite  is  not  a  general  protoplasmic 
irritant,  but  a  selective  drug.     Trje  primary  stimulation  of  the 
nerve-endings  is  followed  by  depression,  which  shows  in  numb- 
ness and  diminished  appreciation  of  pain  and  touch,  i.  e.,  partial 
local  anesthesia.     Since  the  drug  is  highly  selective,  these  effects 
on  nerve-endings  are  also  seen  from  large  doses  of  the  drug  acting 
systemically,  as  when  it  is  administered  by  mouth.     Short  and 
Salisbury  could  get  no  cutaneous  anesthesia  from  a  3  per  cent. 


2 1 8  PHARMACOLOGY   AND    THERAPEUTICS 

solution  of  aconitine ;  and  it  may  be  that  the  stimulating  effect 
is  the  essential  one. 

Alimentary  Tract. — The  taste  is  bitter,  and  from  even  a  very 
dilute  solution  (i  :  500,000  of  aconitine),  the  mouth,  lips,  and 
tongue  may  feel  a  pricking  and  biting  sensation,  followed  by 
numbness.  The  saliva  is  increased  at  first,  largely  reflexly,  as 
the  result  of  the  presence  of  an  offending  substance  in  the  mouth, 
but  partly  from  direct  stimulation  of  the  secretory  nerve-endings ; 
these  are  later  depressed,  the  mouth  becoming  dry  from  the 
absence  of  saliva.  Squibb's  test  for  aconite  is  to  hold  1  dram 
(4  c.c.)  of  a  solution  of  1  :  70  of  the  tincture  in  the  anterior  part 
of  the  mouth  for  one  minute,  then  discharge  it.  A  distinct 
tingling  will  be  apparent  in  ten  to  fifteen  minutes. 

In  the  stomach  and  intestines  the  unpleasant  local  action  may 
result  in  nausea,  vomiting,  and  catharsis,  but  such  effects  are 
unusual  from  therapeutic  doses.  After  absorption,  the  vomit- 
ing center  may  show  increased  sensitiveness,  as  from  digitalis; 
but  in  practice  vomiting  is  rare,  for,  unlike  digitalis,  aconite  is 
not  employed  in  full  doses  for  long  periods. 

Absorption  is  rapid  through  mucous  membranes.  From 
oily  or  alcoholic  preparations  it  is  also  fairly  rapid  through  the 
skin,  hence  liniments  must  be  employed  with  caution.  The 
drug  causes  too  much  pain  for  hypodermatic  use. 

Circulation. — After  a  very  brief  period  of  increased  activity  from 
accelerator  stimulation,  the  heart  becomes  slowed  through  pro- 
longation of  the  diastolic  pause,  and  there  is  diminished  muscular 
contraction  in  systole,  i.  e..  the  heart  does  less  work  and  has  a 
longer  resting  period,  and  there  is  diminished  output  of  blood  and 
a  gradual  lowering  of  blood-pressure.  This  is  the  typical  vagus 
effect;  and  it  must  be  due  to  stimulation  of  the  vagus  center, 
for  it  does  not  occur  if  the  vagi  are  cut  or  after  atropine. 
This  is  followed  by  the  same  stages  as  result  from  digitalis. 

As  a  matter  of  fact,  in  laboratory  animals  aconite  produces 
effects  which  resemble  so  closely  those  of  digitalis  that  one  would 
think  of  the  drugs  as  belonging  to  the  same  pharmacologic  class. 
Following  or  accompanying  the  slowing  there  may  be  sinus 
arhythmia,  heart-block,  or  one  or  other  of  the  manifestations  of 
increased  irritability.  (See  Digitalis.)  It  was  with  aconite 
that  Cushny  discovered  the  phenomenon  of  reversed  or  retro- 
grade rhythm,  in  which  the  auricular  beat  follows  that  of  the 
ventricle  instead  of  preceding  it.  In  toxic  amounts  it  also  con- 
stricts the  arteries  by  stimulation  of  the  vasoconstrictor  center. 

In  therapeutics  it  has  been  assumed  that  pure  vagus  stimula- 
tion might  be  obtained,  as  shown  by  a  slowing  of  the  rate  and  a 
fall  in  arterial  pressure.     But  Mackenzie  (191 1)  gave  tincture  of 


ACONITE  219 

aconite,  beginning  with  5  minims  every  two  hours,  then  10 
minims,  then  15.  Although  the  dose  was  given  for  several  days 
in  many  cases,  not  the  slightest  effect  could  be  detected.  Then, 
at  Cushny's  suggestion,  he  got  Price  to  try  aconitine  in  cases  of 
auricular  fibrillation  in  which  digitalis  proved  effective,  and  in 
cases  of  rapid  heart  due  to  fever  and  other  causes.  Price  care- 
fully pushed  the  drug  until  the  patient  felt  tingling  of  the  tongue 
and  skin,  but  in  not  a  single  instance  did  he  get  any  evidence  of 
a  reaction  on  the  heart  or  blood-vessels. 

And  Rudolf  and  Cole  (191 2),  in  tests  on  55  patients  with  and 
without  fever,  failed  to  get  any  change  in  the  pulse-rate.  They 
gave  as  much  as  4^  minims  of  the  B.  P.  tincture,  equivalent  to 
2%  minims  (0.14  c.c.)  of  the  U.  S.  P.  tincture,  every  ten  to  fif- 
teen minutes  for  8  to  10  doses. 

From  therapeutic  amounts  there  is  no  depression  of  any  part 
of  the  vasoconstrictor  mechanism;  and  the  drug  lowers  arterial 
pressure,  if  at  all,  by  pure  cardiac  depression  and  not  by  dilata- 
tion of  the  arteries. 

Respiratory '. — From  moderate  doses  there  is  stimulation  of 
the  respiratory  center,  with  increased  depth  and  frequency  of 
respiration;  but  from  doses  beyond  therapeutic  there  is  early 
depression  of  the  center,  with  slowing  of  the  respiration,  labored 
breathing,  and  lessening  of  the  intake  of  air.  In  poisoning  there 
may  be  also  some  stimulation  of  the  sensory  vagus  endings  in  the 
lungs  (for  the  accessory  respiratory  muscles  contract  vigorously) , 
and  a  stimulation  of  the  bronchoconstrictor  nerve-endings,  the 
result  being  bronchial  spasm  (Dixon).  Death  takes  place  from 
asphyxia  due  to  paralysis  of  the  respiratory  center.  If  artificial 
respiration  is  maintained,  the  heart  will  continue  to  beat  for 
some  time  after  the  respiratory  center  fails. 

Cerebrum. — This  is  the  last  part  of  the  nervous  system  to  be 
affected,  and  consciousness  is  retained  until  the  final  stages  of 
poisoning.  The  mind  becomes  dulled  only  when  the  patient 
passes  into  collapse. 

Medulla. — The  vagus  center  is  stimulated,  as  already  indi- 
cated; the  vasoconstrictor  center  is  stimulated  by  poisonous  doses, 
but  this  stimulation  soon  passes  into  depression;  the  respiratory 
center  is  at  first  stimulated  but  very  soon  depressed,  and  through 
its  paralysis  death  is  produced.  The  vomiting  center  may  be 
stimulated;  the  heat-regulating  center  may  be  affected  so  that 
temperature  in  fever  is  lowered.  Convulsions  may  occur  in  the 
poisoning,  and  are  due  either  to  asphyxia  or  to  stimulation  of 
the  reflex  centers  of  medulla  and  spinal  cord. 

Peripheral  Nerves. — The  peripheral  ends  of  the  sensory  and 
secretory  nerves  we  have  already  spoken  of.     They  are  strongly 


2  20  PHARMACOLOGY   AND    THERAPEUTICS 

stimulated,  and  later  depressed.  This  effect  is  observed  not  only 
on  local  application,  but  also  after  the  drug  is  absorbed,  for 
aconite  is  selective.  From  a  poisonous  dose  taken  internally 
the  tingling,  and  later  the  numbness,  become  general.  The 
ends  of  motor  nerves  are  also  somewhat  stimulated  and  later 
depressed.  The  ends  of  the  nerves  conveying  heat  and  cold 
sensations  are  affected  in  the  poisoning,  and  cause  chilly  feelings 
regardless  of  any  changes  in  the  cutaneous  circulation  or  in  the 
body  temperature. 

Muscle. — From  large  amounts  there  is  slight  direct  stimula- 
tion of  cardiac  muscle  (already  referred  to)  and  of  voluntary 
muscle,  as  indicated  by  its  occurrence  after  curare.  This  is  of  no 
therapeutic  importance. 

Temperature. — Aconite  is  antipyretic,  i.  e.,  it  tends  to  induce 
a  fall  of  temperature  in  fever,  but  it  is  not  strongly  so.  There 
seems  to  be  a  stimulation  of  the  heat-regulating  center,  the  cen- 
ter which  sets  going  the  mechanisms  to  bring  an  abnormal  tem- 
perature to  normal.  (See  Antipyretics.)  The  fall  in  tempera- 
ture results  from  lessened  production  of  heat,  owing  to 
diminished  activity  of  the  circulation,  but  there  is  also  some  in- 
crease of  heat  loss  from  a  moderate  dilatation  of  the  skin  vessels, 
and  perhaps  from  sweating. 

Secretions. — The  saliva  is  increased,  as  already  mentioned, 
partly  reflexly  from  the  mouth,  and  partly  through  stimulation 
of  the  secretory  nerve-ends.  The  sweat  is  also  increased,  but 
free  sweating  is  irregular  and  not  marked.  It  is  believed  to  be 
due  to  stimulation  of  the  nerve-endings  in  the  sweat-glands,  and 
slightly  to  dilatation  of  the  skin  vessels.  At  best,  aconite  is  a 
mild  and  uncertain  diaphoretic. 

Excretion. — The  active  principles  are  excreted  mostly  in  the 
urine;  traces  have  also  been  found  in  other  secretions,  as  the 
saliva,  gastric  juice,  bile,  and  sweat.     The  kidneys  are  unaffected. 

Toxicology. — Poisoning  from  doses  by  mouth  is  readily 
recognized  by  the  prompt  tingling  of  mouth,  lips,  and  tongue, 
followed  by  numbness.  There  may  also  be  nausea,  vomiting, 
diarrhea,  and  pain  in  the  stomach.  After  absorption  the  tin- 
gling may  become  general  over  the  whole  surface  of  the  body, 
being  first  noticed  in  the  finger-tips.  The  pupil  is  dilated  and 
the  vision  deranged,  with  mistiness  of  the  sight  or  diplopia. 
Early  in  the  poisoning  there  are  the  peculiar  chilly  sensations. 
The  breathing  may  be  asthmatic,  labored,  from  constriction  of 
the  bronchi,  and  there  may  be  cyanosis. 

The  circulatory  changes  we  have  spoken  of.  Blood-pressure 
is  lowered,  then  raised,  then  again  lowered,  and  collapse  follows. 
Death  takes  place  usually  from  asphyxia  caused  by  respiratory 


ACONITE  221 

paralysis,  but  perhaps  also  from  ventricular  fibrillation  or  heart- 
block.  It  takes  about  0.2  mg.  of  aconitine  per  kilo  to  kill  a  rabbit 
(Eden). 

The  treatment  of  poisoning  by  aconite  consists  in  washing  out 
the  stomach,  keeping  patient  in  absolute  repose,  keeping  up 
bodily  heat,  and  treating  the  condition  of  the  heart  as  indicated 
under  Digitalis.  Atropine  is  said  to  be  particularly  antidotal, 
because  it  not  only  checks  vagus  activity,  but  also  stimulates 
the  respiratory  center  and  depresses  the  constrictor  endings  in 
the  bronchial  muscles,  thus  overcoming  the  labored  breathing. 

Therapeutics. — Aconite  is  a  drug  that,  in  the  light  of  recent 
research,  has  doubtful  therapeutic  value.  Externally  it  is  used  in 
liniments  to  allay  pain,  as  in  neuralgia,  lumbago,  and  muscular 
pains.  It  is  applied  to  the  gums  in  toothache.  Internally  its 
value  may  be  considered  problematic.  It  has  been  employed 
extensively  to  slow  and  quiet  a  heart  which  is  overacting  from 
any  cause,  for  example,  in  nervous  excitement  or  in  sthenic 
fevers  with  quick  pulse  and  high  arterial  pressure.  Also  to 
reduce  arterial  pressure  when  very  high,  as  in  chronic  nephritis 
or  convulsive  conditions,  as  uremia  or  eclampsia. 

In  the  fevers  of  children,  and  in  adults  at  the  onset  of  acute 
pharyngitis  or  tonsillitis  or  bronchitis,  aconite  has  been  employed 
empirically.  Its  supposed  beneficial  effects  in  these  cases  have 
been  attributed  to  its  antipyretic  action,  and  perhaps  to  its 
power  to  quiet  the  rapid  heart  and  lower  the  heightened  blood- 
pressure  which  is  associated  with  the  onset  of  a  cold.  It  is  much 
less  used  in  fever  than  formerly. 

It  is  sometimes  administered  internally  in  trifacial  neuralgia, 
with  alleged  relief  of  the  pain. 

Administration. — For  adults,  a  customary  dose  is  3  to  5 
minims  of  the  tincture  given  every  hour  for  three  or  four  doses. 
It  is  frequently  given  in  tablets,  each  representing  3  minims  of 
the  tincture.  For  children  the  tincture  may  be  added  to  the 
liquor  ammonii  acetatis  to  make  a  fever  mixture.  It  is  irra- 
tional therapeutics  to  administer  atropine  or  belladonna  at  the 
same  time  as  aconite,  for  atropine  paralyzes  the  vagus  endings 
and  checks  the  vagus  effect  upon  the  heart. 

Delphinium  (larkspur)  and  staphisagria  (stavesacre)  are 
botanic  and  pharmacologic  relatives  of  aconite,  but  they  are 
limited  in  their  therapeutic  use  to  the  destruction  of  pubic  and 
head  lice.  A  mixture  of  equal  parts  of  the  tincture  of  delphinium 
and  ether  is  a  favorite  prescription.  It  should  be  specifically 
labeled  ''Poison."  The  poisonous  symptoms  are  the  same  as 
those  of  aconite. 


22  2  PHARMACOLOGY  AND   THERAPEUTICS 

VERATRUM 

The  dried  rhizome  and  roots  of  Veratrum  viride,  American 
hellebore,  and  of  Veratrum  album,  white  hellebore  (Fam.  Lilia- 
cece).  V.  viride  is  a  tall,  coarse  herb  of  wet  regions,  growing 
in  all  parts  of  North  America,  and  V.  album  is  found  in  Europe 
and  Asia. 

Constituents. — There  is  great  confusion  about  the  constitu- 
ents of  these  drugs.  Veratrine  is  a  term  which  has  been  applied 
to  several  distinct  alkaloids  or  mixtures  of  alkaloids.  Wright 
and  Luff,  and  also  Couerbe,  applied  it  to  an  alkaloid  that  is  also 
known  as  veratridine;  Merck,  Bosetti,  Ahrens,  and  others,  to  an 
alkaloid  known  also  as  cevadine;  the  United  States  Pharmacopoeia 
applies  it  to  a  variable  mixture  of  several  alkaloids  which  are 
yielded  by  an  entirely  different  plant.  Which  of  these  is  em- 
ployed in  pharmacologic  investigations  has  not  always  been 
stated  in  the  reports. 

Veratrum  viride  contains  cevadine  as  its  chief  constituent. 
It  also  contains  veratridine,  jervine,  rubijervine  (acrid),  pseudo- 
jervine  (inactive),  and  some  irritant  resin.  Wood  says  that  it 
contains  traces  of  proto veratrine. 

Veratrum  album  owes  its  essential  activity  to  protoveratrine. 
It  contains  also  jervine,  rubijervine,  and  acrid  resin,  but  not 
cevadine. 

Veratrine,  U.  S.  P.,  contains  cevadine  as  its  essential  con- 
stituent, and  also  cevadilline,  sabadine,  sabadinine,  and  vera- 
tridine. It  is  obtained  from  the  seeds  of  Asagrcea  officinalis,  or 
sabadilla  (Fam.  Liliacece). 

Veratrine  and  veratrum  viride  depend  essentially  on  cevadine 
for  their  activity,  while  veratrum  album  depends  on  protro- 
veratrine. 

Preparations  and  Doses. — Veratrum,  2  grains  (0.13  gm.). 
Fluidextract,  2  minims  (0.13  c.c).  Tincture,  10  per  cent.,  20 
minims  (1.3  c.c). 

Veratrine,  the  official  mixture  of  alkaloids  from  sabadilla 
seeds,  is  assigned  the  dose  of  3V  grain  (0.002  gm.)  by  the 
Pharmacopoeia,  but  it  is  a  drug  of  too  great  power  and  uncer- 
tainty for  internal  use.  For  external  use  jt  has  two  official 
preparations:  the  ointment,  4  per  cent.,  and  the  oleate,  2  per  cent. 

In  the  Pharmacopoeia  of  1890  the  preparations  of  veratrum 
were  made  from  Veratrum  viride  only,  and  were  found  to  act 
with  great  irregularity  and  uncertainty  (H.  C.  Wood,  Jr.).  In 
the  Pharmacopoeia  of  1900  either  of  the  veratrums,  V.  viride  or 
V.  album,  maybe  used,  thus  increasing  the  already  great  chances 
of  variability. 

Pharmacologic  Action. — Locally,  all  veratrum  preparations 


VERATRUM  223 

are  very  irritant,  both  because  of  their  alkaloids  and  because  of 
the  presence  of  acrid  resin.  If  the  dust  is  inhaled,  it  causes  vio- 
lent sneezing  and  coughing.  If  a  preparation  is  swallowed  in- 
sufficiently diluted,  it  may  cause  vomiting;  or  if  not  vomited, 
diarrhea  and  colicky  pains. 

Cevadine  (frequently  called  veratrine)  is  more  irritant  locally 
than  aconitine,  but  acts  like  aconitine  on  the  vagus  and  vaso- 
constrictor centers.  It  is  also  a  general  muscular  stimulant, 
inducing  increased  irritability  and  increased  power  in  all  kinds 
of  muscle.  In  experiments  with  a  frog's  gastroc- 
nemius, for  example,  it  causes  increased  quick- 
ness and  length  of  contraction,  increased  lifting 
and  sustaining  power,  and  lessened  fatigue. 
That  this  is  a  pure  muscular  stimulation  is 
shown  by  its  taking  place  after  the  end-plates 
are  paralyzed  by  curare.  But  there  is  a  pecu-  Flmuscie_ curve^1 
liar  phenomenon  in  the  muscular  relaxation,  for 
this  is  found  to  take  place  very  slowly  indeed,  so  that  quite  an 
interval  elapses  before  the  muscle  is  ready  to  contract  again. 
It  might  be  thought  that  this  tardy  relaxation  is  due  to  a  loss  of 
muscle  elasticity,  but  this  is  not  the  case,  and  that  the  muscle  is  in 
an  active,  though  diminishing,  state  of  contraction  is  shown  by  its 
ability  to  sustain  weight  during  the  relaxation,  and  by  the  con- 
tinuous production  of  heat,  which  indicates  that  work  is  being 
done.  This  reaction  of  muscle,  which  occurs  also  from  other 
drugs,  is  known  in  pharmacology  as  the  "veratrine  action." 
From  therapeutic  doses  this  effect  on  relaxa- 
tion is  not  observed,  while  there  is  distinct 
stimulation  of  striated  muscle.  Hence,  it  is 
evident  that  cevadine  (veratrine)  is  a  muscular 
stimulant,  and  not,  as  at  one  time  taught,  a 
muscular  depressant. 
Fig.  29.  — Veratrine  Protoveratrine   resembles  aconitine  in  its 

muscle  curve.  effects   upon    the    circulation,    though   it   is 

nearly  twice  as  toxic  (o.n  mg.  per  kilo  in 
rabbit,  Eden).  It  is  not  so  irritant  locally  as  cevadine,  and  the 
irritation  may  be  followed  by  local  anesthesia.  It  stimulates 
strongly  the  vagus  center,  and  in  large  doses  the  vasoconstrictor 
center  and  the  cardiac  muscle,  the  stimulation  being  followed  by 
depression  of  these  structures  in  the  same  order.  Like  cevadine, 
it  is  a  stimulant  of  muscle,  increasing  its  irritability  and  the 
strength  and  completeness  of  its  contraction;  but  the  relaxation 
is  prompt  and  not  prolonged,  as  with  cevadine,  and  muscle 
fatigue  sets  in  early. 

This  is  the  main  constituent  of  Veratrum  album,  and  repre- 
sents its  action;  but  because  of  the  presence  of  more  acrid  resin, 


224  PHARMACOLOGY  AND   THERAPEUTICS 

preparations  of  Veratrum  album  are  more  irritant  locally  than 
those  of  Veratrum  viride. 

Circulation. — After  therapeutic  doses  of  any  of  the  prepara- 
tions there  is  pure  slowing  of  the  heart  by  vagus  stimulation, 
with  perhaps  slight  stimulation  of  muscle.  After  toxic  doses 
there  are:  excessive  slowing,  with  perhaps  irregularity  or  inter- 
mittence  from  vagus  stimulation,  then  quickening  and  strength- 
ening of  the  heart,  with  vasoconstriction  and  raised  arterial 
pressure,  then  cardiac  exhaustion  and  collapse.  Death  takes 
place  with  asphyxia  from  paralysis  of  the  respiratory  center, 
which  is  contributed  to  by  the  heart  failure. 

Toxicology. — The  poisoning  and  its  treatment  are  those  of 
aconite,  but  veratrum  is  much  more  likely  to  be  expelled  by 
vomiting,  owing  to  its  very  irritant  local  action  in  the  stomach. 

Therapeutics. — Veratrine  has  been  used  externally  as  a 
slowly  acting  anesthetic  in  muscular  pains  and  neuralgia,  espe- 
cially in  facial  neuralgia.  But  its  primary  irritation  prevents  it 
from  being  a  favorite  preparation;  and  as  it  may  be  absorbed 
through  the  skin,  especially  when  in  the  form  of  the  oleate,  its 
local  use  is  not  without  danger. 

Veratrum  is  used  to  slow  a  rapid  heart  and  to  quiet  an  over- 
acting one,  its  chief  employment  being  in  eclampsia.  This  is  a 
condition  of  poisoning  associated  with  pregnancy,  and  it  is  mani- 
fested by  convulsions  which  are  usually,  though  not  always, 
preceded  by  high  blood-pressure.  That  eclampsia  is  a  very 
serious  condition,  and  one  in  which  the  best  of  drugs  can  be  none 
too  good,  is  well  shown  by  Ryder's  report  in  October,  1905,  that 
in  thirteen  months  at  the  Sloane  Maternity  Hospital  there  had 
been  37  cases  of  eclampsia,  with  the  deaths  of  13  mothers  and 
19  infants;  and  by  McPherson's  statistics  that  in  250  cases  of 
eclampsia  at  the  Lying-in  Hospital  there  were  30  per  cent,  of 
maternal  deaths  and  44  per  cent,  of  fetal  or  infant  deaths. 

In  eclampsia  very  large  doses  of  veratrum  have  been  em- 
ployed, and  at  times  with  an  astounding  but  valuable  depression 
of  the  arterial  tension.  Starling  and  Hirst,  independently,  have 
made  studies  of  the  arterial  pressure  in  pregnant  women,  and 
both  have  found  that  high  pressure  means  toxemia.  In  one  of 
Hirst's  eclamptic  cases  the  pressure  was  320  mm.  of  mercury. 
Therefore  it  would  appear  that  the  lowering  of  blood-pressure  is 
the  real  desideratum  in  veratrum  treatment.  The  drug,  how- 
ever, is  not  an  arterial  dilator,  therefore  it  might  well  be  ac- 
companied by  nitroglycerin ;  and  caution  must  be  employed  not 
to  overdo  the  depression.  The  author's  attention  has  been 
called  to  the  occurrence  of  collapse  in  a  number  of  eclampsia  cases 
following  the  administration  of  veratrum  in  large  doses  for  two 
or  three  days. 


NITRITES  2  25 

Arterial  Dilators 

The  drugs  most  employed  to  dilate  the  arteries  are  those  of 
the  nitrite  group,  and  to  a  slight  extent  chloral  hydrate  and 
potassium  iodide. 

NITRITES 

The  pharmacologic  group  of  nitrites  includes  the  nitrites  of 
amyl,  ethyl,  and  sodium,  and,  in  addition,  certain  drugs  which 
are  not  nitrites,  but  yield  nitrites  by  their  decomposition.  The 
alkali  nitrates  have  no  effect  upon  arterial  pressure,  but  potas- 
sium nitrate  is  a  salt  which  forms  nitrites  when  it  is  burned, 
thought  it  does  not  do  so  in  the  body;  and  nitroglycerin,  erythrol 
tetranitrate,  and  mannitol  hexanitrate  are  organic  nitrates  which 
liberate  nitrites  in  the  blood. 

Preparations  and  Doses. — Amyl  nitrite,  amylis  nitris,  C5Hn- 
N02,  dose,  2-5  minims  (0.13-0.3  c.c),  is  an  unstable  liquid  with  a 
banana-like  ethereal  odor.  It  is  very  volatile,  and  decomposes 
slowly  when  exposed  to  air  and  light.  For  convenience,  it  is  sold 
in  capsules  or  ampules  of  dark  glass,  containing  two,  three,  four, 
or  five  minims.  The  drug  is  employed  by  inhalation,  the  vapor 
being  liberated  by  breaking  one  of  these  capsules  in  a  handker- 
chief or  piece  of  gauze. 

Sodium  nitrite,  sodii  nitris,  NaN02,  dose,  1  grain  (0.06  gm.), 
is  a  non-volatile  and  non-explosive  deliquescent  salt,  which  is 
freely  soluble  in  water  (1.4  parts).  It  has  an  affinity  for  oxygen, 
and  is  used  in  chemistry  as  a  deoxidizing  agent.  In  the  air  it 
gradually  oxidizes  to  nitrate  and  loses  its  efficiency;  and  because 
of  this,  is  the  least  certain  of  the  group.  When  given  during  the 
digestive  period,  i.  e.,  while  there  is  free  HC1  in  the  stomach,  it 
sets  free  nitrous  acid,  which  is  not  only  irritating  to  the  stomach, 
but  may  be  somewhat  oxidized  and  rendered  inert  before  absorp- 
tion. 

Nitroglycerin,  glyceryl  trinitrate,  trinitrin,  or  glonoin,  C3H5- 
(N03)3,  is  the  volatile,  highly  explosive  liquid  which  is  used  in 
the  manufacture  of  dynamite.  It  is  decomposed  and  rendered 
non-explosive  by  strong  alkalis.  Its  dose  is  yito  grain  (0.006 
gm.) .  Its  only  official  preparation  is  the  spirit  of  glonoin  (spiritus 
glycerylis  nitratis),  an  alcoholic  solution  of  1  per  cent,  by  weight 
of  nitroglyercin,  the  dose  of  which  is  1  minim  (0.06  c.c),  which 
contains  about  j%-$  grain  (0.0005  gm-)-  It  is  most  commonly 
employed  in  the  form  of  tablet  triturates  or  hypodermatic 
tablets,  but,  because  of  its  volatility,  these  may  be  of  variable 
strength  and  should  be  kept  in  closed  bottles. 

Erythrol    tetranitrate,   CH2CH.CH2(N03)4,    is    an    unofficial, 
slightly  volatile  solid,  which  is  insoluble  in  water  and  is  highly 
15 


2  26  PHARMACOLOGY  AND  THERAPEUTICS 

explosive.  A  druggist  is  reported  to  have  had  his  hand  blown 
off  on  rubbing  it  in  a  mortar.  The  dose  is  i  grain  (0.06  gm.), 
in  tablets,  which  keep  best  when  coated.     It  is  rather  expensive. 

Spirit  of  nitrous  ether,  sweet  spirit  of  niter,  is  an  alcoholic 
solution  of  4  per  cent,  by  weight  of  ethyl  nitrite.  Its  dose  is 
30  minims  (2  c.c),  well  diluted  with  water.  It  is  too  mild  a 
preparation  to  use  as  a  general  arterial  dilator,  and  it  is  employed 
chiefly  in  colds  and  slight  fevers  as  a  diuretic.  It  is  possible 
that  in  these  conditions  it  may  be  of  use  in  counteracting  the 
tendency  to  raised  blood-pressure  that  goes  with  fever. 

Potassium  nitrate,  KN03,  saltpeter,  niter,  is  a  constituent  of 
gunpowder,  but  is  non-explosive.  It  is  soluble  in  3.6  parts  of 
water.  The  solution  is  used  to  saturate  unsized  (filter)  paper  or 
the  leaves  of  stramonium  or  tobacco;  and  these,  when  dry,  are 
burned,  and  the  fumes  inhaled  for  the  relief  of  bronchial  asthma. 
On  burning,  the  nitrate  liberates  nitrites,  which  check  the  asth- 
matic attack  by  inducing  relaxation  of  the  spasmodically  con- 
tracted bronchial  muscles.  The  nitrate  by  itself  or  simply 
mixed  with  other  drugs  does  not  burn  readily.  Some  of  the 
papers  used  in  cigarette-making  are  impregnated  with  niter  to 
make  them  burn  evenly  without  bursting  into  a  flame;  in  this 
case  the  niter  may  incidentally  serve  the  useful  purpose  of 
antagonizing  the  primary  rise  in  blood-pressure  caused  by  nico- 
tine. 

Pharmacology. — Almost  the  sole  use  of  nitrites  in  medicine  is 
to  relax  constricted  arteries  and  constricted  bronchi. 

The  Arteries. — If  a  nitrite  is  added  to  the  liquid  used  in  per- 
fusing an  isolated  viscus  or  a  severed  limb,  the  flow  through  the 
viscus  or  limb  is  greatly  increased,  and  even  doubled  or  trebled. 
It  is  evident,  therefore,  that  the  drug  acts  peripherally  to  dilate 
the  arterioles  to  a  marked  degree.  Again,  if  an  animal  is  ar- 
ranged so  that  the  blood  of  the  carotid  artery  may  reach  the 
medullary  centers,  but  is  prevented  from  getting  into  the  general 
circulation,  the  injection  of  a  nitrite  into  the  carotid  does  not 
produce  a  fall  in  arterial  pressure.  Therefore  the  central  action 
is  not  a  factor  in  the  lowering  of  the  pressure,  i.  e.,  there  is  neither 
depression  of  the  vasoconstrictor  center  nor  stimulation  of  the 
vasodilator  center.  How  much  of  the  peripheral  action  is  on  the 
ends  of  the  nerves  and  how  much  on  the  arterial  muscles  has  not 
been  satisfactorily  demonstrated;  but  that  the  muscular  action 
is  the  chief  one  is  indicated  by  the  dilatation  of  the  pulmonary 
arteries,  which  have  no  vasomotor  nerves.  So  the  essential 
action  is  direct  depression  of  the  arterial  muscles.  The  nitrites, 
therefore,  are  true  arterial  dilators.  Cameron  ascertained  that 
on  injecting  y^g-  grain  (0.6  mg.)   of    nitroglycerin  along  with 


Aur. 


Ven. 


B.  P. 


Fig.  30. — Nitroglycerin,  0.3  c.c.  of  the  1  per  cent,  spirit  per  kilo,  promptly 
reduced  arterial  pressure  from  105  to  60,  and  this  was  followed  by  an  increase  in 
rate  from  126  to  about  150.     (Tracing  made  by  Dr.  C.  C.  Lieb.) 


NITRITES 


227 


8W0  grain  (0.0075  mg.)  of  epinephrine,  equivalent  to  -| 
minim  (0.008  c.c.)  of  the  solution  of  adrenaline,  there  was  no 
essential  rise  or  fall  in  arterial  pressure,  i.  e.,  these  amounts 
practically  neutralized  each  other  physiologically.  The  action 
of  the  nitrites  is  most  marked  on  the  splanchnic  arteries,  but  it  is 
also  pronounced  in  the  arteries  of  the  limbs,  and  in  the  cerebral, 
coronary,  and  pulmonary  arteries.  In  arteriosclerosis  the  fall 
in  arterial  pressure  is  not  so  readily  produced,  and  when  pro- 
duced, may  be  maintained  for  a  longer  time  than  normally. 
Of  the  surface  vessels,  those  of  the  head  and  neck,  the  blushing 
area,  are  especially  dilated. 

The  veins  are  also  somewhat  relaxed,  but  this  has  not  been 
shown  to  have  any  therapeutic  importance. 

The  Heart. — On  the  isolated  heart  ordinary  doses  have  no 
effect,  whether  the  ends  of  the  vagus  and  accelerator  nerves  are 
paralyzed  or  not.  But  larger  doses  depress  the  vagus,  and  there- 
fore tend  to  increase  the  tone  and  contractility  of  the  heart. 

With  the  fall  in  arterial  pressure  from  an  ordinary  dose  the 
heart's  rate  is  accelerated,  and  after  amyl  nitrite  may  increase 
20  or  30  beats  a  minute.  The  increase  is  due  to  vagus  depres- 
sion, for  if  the  vagus  endings  are  first  paralyzed  by  atropine,  the 
nitrite  does  not  cause  any  additional  increase  in  the  rate  of  the 
heart.  The  question  arises,  "Is  the  vagus  depression  due  to 
the  direct  action  of  the  drug  upon  the  center,  or  is  it  the  regular 
reflex  depression  which  accompanies  lowered  arterial  pressure?" 
Sollman  brings  forward  some  evidence  that  it  is  due  to  direct 
depression  of  the  vagus  center  by  the  drug.  He  finds  that  if  the 
drug  is  allowed  to  act  upon  the  general  circulation,  but  pre- 
vented from  reaching  the  brain,  there  is  no  increase  in  rate, 
though  the  general  arterial  pressure  is  lowered;  and  if  the  drug  is 
confined  to  the  cerebral  circulation,  the  increased  rate  occurs 
without  a  lowering  in  the  general  arterial  pressure;  other  pharma- 
cologists, however,  consider  it  secondary  to  the  fall  in  pressure. 

The  effects  of  nitrites  upon  the  circulation  are,  therefore — 
(1)  Depression  of  the  arterial  muscles,  resulting  in  dilatation  of 
the  arteries;  (2)  increased  rate  of  the  heart's  beat;  (3)  perhaps 
increased  tone  and  strength  of  the  heart. 

With  all  the  stronger  members  of  the  series,  the  arterial 
pressure  shows  a  marked  fall,  and  then  gradually  returns  almost 
or  entirely  to  where  it  was  before.  But  the  drugs  differ  in  their 
rapidity  of  action. 

Amyl  nitrite  is  given  by  inhalation.  The  arterial  pressure  in 
normal  animals  falls  to  the  maximum  degree  almost  instantly, 
rises  again  to  the  original  pressure  in  two  to  five  minutes,  and 
shows  complete  restoration  in  from  fifteen  to  twenty  minutes. 


228  PHARMACOLOGY  AND  THERAPEUTICS 

In  human  cases  with  systolic  pressure  above  200  mm.  Hg  the 
author  has  found  that  after  5  minims  of  amyl  nitrite  the  change 
in  pressure  varies  considerably.  It  might  drop  as  much  as  70 
mm.,  to  rise  again  almost  to  the  original  height  in  about  five 
minutes.  But  so  marked  a  fall  in  pressure  is  unusual,  the  change 
being  mostly  between  20  and  40  mm.  In  some  of  these  high- 
pressure  cases  the  response  is  very  little,  and  in  a  few  cases  there  is 
actually  a  rise  in  pressure  of  10  to  20  mm.  The  action  of  amyl 
nitrite  is  too  fleeting  for  use  except  in  emergencies. 

Nitroglycerin  is  given  by  mouth  or  hypodermatically.  and  in 
either  case  is  almost  instantly  absorbed.  The  fall  in  pressure 
begins  in  one-half  to  three  minutes,  reaches  its  maximum  in  five 
to  fifteen  minutes,  and  disappears  in  one-half  to  one  hour.  In 
conditions  of  general  arteriosclerosis  the  effect  sometimes  lasts 
several  hours,  and  sometimes  there  is  no  change  in  pressure  at  all. 

Sodium  nitrite  is  given  by  mouth,  and  is  less  rapidly  absorbed. 
It  has  been  reported  by  G.  A.  Gibson  and  others  as  less  effective 
than  nitroglycerin,  but  recently  several  investigators  (Matthews, 
and  Wallace  and  Ringer,  and  Lawrence)  have  found  it  just  as 
active  as  the  other  preparations,  though  slower  in  its  action.  Its 
effects  come  on  in  five  to  thirty  minutes,  reach  their  maximum 
in  twenty  to  eighty  minutes,  and  are  completely  over  in  one  to 
two  hours.  In  solution  the  nitrite  changes  to  nitrate  on  expo- 
sure to  air,  and  this  may  account  for  the  adverse  clinical  reports. 

Erythrol  Ictranitrate  is  administered  by  mouth,  and  is  likely 
to  be  more  slowly  absorbed  and  more  slowly  decomposed  by  the 
blood.  As  a  consequence,  its  effects  are  more  gradual  in  their 
development.  The  drop  in  pressure  begins  in  five  to  thirty 
minutes,  reaches  its  maximum  one-half  to  two  hours  later,  and 
disappears  in  two  to  five  hours. 

Mannitol  licxanitrate  has  an  effect  about  the  same  as  that  of 
erythrol. 

Wallace  and  Ringer  found  that  with  any  member  of  the 
series  the  greater  the  dose,  the  greater  was  the  fall  in  pressure. 
In  one  of  their  cases  ^  grain  of  nitroglycerin  reduced  the 
pressure  from  210  to  60  mm.  Hg  in  ten  minutes,  the  pressure 
rebounding  to  168  mm.  in  four  minutes,  and  reaching  its  original 
figure  in  fifty  minutes.  In  another  patient  sodium  nitrite  caused 
the  pressure  to  fall  from  210  to  100  mm.  In  cases  with  high 
arterial  pressure  the  author  has  never  secured  such  striking 
results,  even  from  the  administration  of  5V  grain  of  nitro- 
glycerine hypodermatically  every  two  minutes  for  five  doses. 

Blood. — After  enormous  doses  the  hemoglobin  is  reduced  and 
its  power  of  liberating  oxygen  lessened  by  the  formation  of 
methemoglobin  and  nitric  oxide  hemoglobin.     But  in  the  thera- 


NITRITES 


229 


peutic  use  of  the  drug  this  reduction  is  never  enough  to  produce 
ill  effects,  and  even  after  very  large  therapeutic  amounts  no 
methemoglobin  has  been  present  in  the  blood. 

Respiratory  System. — The  nitrites  stimulate  the  respiratory 
center,  so  that  breathing  is  deeper  and  more  rapid.  This  may 
be  because  of  increased  supply  of  carbon  dioxide  from  improved 
medullary  circulation.  From  very  large  doses  there  is  later  a 
depression  of  the  center  and  asphyxia.  In  bronchial  asthma 
nitrites  may  be  effective  in  overcoming  the  spasm  of  the  bronchial 
muscles.  This  is  a  direct  muscular  effect,  and  is  not  antagonistic 
to  the  action  of  epinephrine  in  the  same  condition.  (When  amyl 
nitrite  is  inhaled,  it  may  cause  a  momentary  reflex  stoppage  of 
respiration  from  irritation  of  the  respiratory  passages,  but  this  is 
of  no  significance,  for  the  respiration  goes  on  again  immediately.) 

Cerebrum. — There  is  no  direct  action  on  the  brain  structures. 
The  cerebral  arteries  are  dilated  along  with  all  others,  and 
either  because  of  this  or  of  the  general  fall  in  pressure,  there  may 
be,  after  amyl  nitrite  or  nitroglycerin,  dizziness,  blurring  of 
the  sight,  and  a  momentary  faintness.  Frequently  after  nitro- 
glycerin and  erythrol  tetranitrate  there  is  such  severe  occipital 
headache  that  the  administration  requires  to  be  stopped.  In 
animal  experiments  convulsions  of  cerebral  origin  have  been 
noted  after  large  doses. 

Medulla. — The  respiratory  center  is  somewhat  stimulated. 
The  vagus  center  is  depressed. 

Eye. — Besides  the  temporary  blurring  of  the  sight,  which  is 
due,  perhaps,  to  dilatation  of  the  retinal  arteries,  dark  objects 
may  appear  to  be  surrounded  by  yellow  and  blue  rings. 

Muscle. — Other  muscles  are  not  so  much  depressed  as  those 
of  the  arteries,  yet  in  bronchial  asthma  the  bronchial  muscles 
may  be  enough  depressed  to  lessen  their  spasmodic  contraction 
and  bring  relief.  This  is  commonly  brought  about  by  the  inhala- 
tion of  the  fumes  from  burning  potassium  nitrate.  Occasionally 
spasm  of  the  ureter  or  common  bile-duct  from  the  presence  of  a 
stone  has  been  overcome  by  nitroglycerin. 

Temperature  may  be  lowered,  owing  to  dilatation  of  the 
cutaneous  vessels  and  the  accompanying  sweating,  but  this  is 
not  a  marked  effect. 

Excretion  is  by  the  kidneys,  chiefly  as  nitrates.  After  large 
amounts  of  nitroglycerin  this  may  appear  unchanged.  The  dose 
is  too  small  to  have  any  appreciable  effect  upon  the  amount  of 
the  nitrogen  elements  of  the  urine. 

Kidneys. — With  the  nitrites,  any  change  in  the  amount  of 
urinary  excretion  depends  upon  the  relation  between  the  fall 
in  general  blood-pressure  and  the  dilatation  of  the  renal  arteries. 


230  PHARMACOLOGY  AND  THERAPEUTICS 

The  effect  is  not  constant,  though  in  some  cases  marked  diuresis 
will  follow  nitrite  administration. 

Toxicology. — It  is  a  common  thing  for  therapeutic  doses  of 
amyl  nitrite  or  nitroglycerin  to  be  followed  immediately  by  a 
pounding  heart,  flushing  of  the  face  and  neck,  and  throbbing 
and  fulness  in  the  head,  with  a  feeling  "as  if  the  top  of  the  head 
were  coming  off."  In  addition  there  may  be  confusion  of  ideas, 
blurring  of  the  sight,  dizziness,  and  a  feeling  of  faintness.  Such 
effects  are  distressing  to  the  patient,  but  are  quickly  recovered 
from.  Except  for  the  flushing  of  the  face,  they  are  not  nearly  so 
striking  when  the  patient  is  lying  down,  and  would  seem  to  be 
due  to  low  cerebral  blood-pressure.  Occasionally  large  doses 
produce  cyanosis  and  collapse.  A  student  in  our  laboratory 
fainted  after  the  inhalation  of  5  minims  of  amyl  nitrite.  He  was 
in  the  upright  position  when  the  drug  was  administered,  and  his 
systolic  pressure  had  been  recorded  as  only  88  mm.  On  the 
other  hand,  D.  D.  Stewart  gave  a  man  50  minims  of  a  10  per 
cent,  solution  of  nitroglycerin  four  times  a  day — i.  e.,  20  grains 
of  nitroglycerin  in  a  day — without  untoward  effects.  Very 
large  doses  have  been  given  to  animals  without  causing  death, 
and  there  are  no  reported  cases  of  death  in  man.  Any  nitrite 
may  be  followed  by  a  headache,  but  persistent  severe  headache 
is  most  common  with  nitroglycerin  or  erythrol  tetranitrate. 

Therapeutics. — 1.  To  lower  abnormally  high  general  arterial 
pressure,  as  in  chronic  nephritis,  the  dose  being  administered  from 
three  times  a  day  to  every  hour.  It  is  especially  prone  to  fail  in 
cases  with  edema.  But  it  must  be  noted  that  in  cases  with 
long-continued  high  arterial  pressure  it  is  not  considered  wise  to 
bring  the  arterial  pressure  down  to  normal.  For  the  high  pres- 
sure may  really  be  a  response  to  a  need  of  one  or  other  organ 
for  a  greater  supply  of  blood.  In  nephritis,  for  example,  the 
lowering  of  a  chronically  high  pressure  may  result  in  suppression 
of  urine.  On  account  of  the  ephemeral  action  of  the  drug,  com- 
parative daily  blood-pressure  tests  should  follow  the  doses  at 
a  fixed  interval  of  time. 

2.  To  lessen  peripheral  resistance  in  some  cases  of  weak  heart, 
as  in  aortic  insufficiency. 

3.  To  dilate  the  peripheral  arteries  in  local  vasomotor  spasm, 
as  in  Raynaud's  disease  and  erythromelalgia. 

4.  To  relax  the  coronary  arteries  in  angina  pectoris.  The 
drug  may  be  indicated  even  if  the  general  blood-pressure  is  not 
high;  but  it  is  said  to  be  contraindicated  in  marked  coronary 
sclerosis  with  myocarditis. 

5.  To  relax  the  bronchial  muscles  in  asthma,  especially  by 
burning  niter. 


TO  DECREASE  THE  VOLUME  OF  THE  BLOOD       23 1 

6.  As  a  diuretic  and  diaphoretic  in  colds  and  mild  fevers — the 
spirit  of  nitrous  ether,  the  alcohol  of  the  spirit  being  probably 
of  as  much  value  as  the  ethyl  nitrite. 

7.  Amyl  nitrite  has  also  been  employed  to  overcome  chloroform 
collapse.  This  is  on  the  theory  that  it  lessens  peripheral  resist- 
ance and  spares  the  exceedingly  weak  heart.  The  author  has 
restored  mice  by  amyl  nitrite  when  they  were  apparently  almost 
dead  from  chloroform.  According  to  Miihlberg  and  Kramer, 
it  is  effective  in  preventing  the  stoppage  of  the  heart  in  the  first 
or  second  stages  of  ether  or  chloroform  anesthetization.  Yet 
some  experiments  with  chloroform  containing  2  per  cent,  of 
amyl  nitrite  have  shown  this  mixture  to  be  more  toxic  than 
chloroform  alone,  so  the  subject  needs  investigation. 

Administration. — For  immediate  and  intense  effect,  amyl 
nitrite  by  inhalation.  For  general  arterial  dilatation,  nitrogly- 
cerin, which  acts  almost  as  promptly  by  mouth  as  when  given 
hypodermatically,  or  sodium  nitrite  or  erythrol  tetranitrate. 
For  bronchial  relaxation,  inhalation  of  amyl  nitrite,  or  the  fumes 
of  burning  potassium  nitrate,  or  nitroglycerin  by  mouth  or  hypo- 
dermatically. "Asthma  powders"  usually  contain  potassium 
nitrate  with  stramonium,  lobelia,  tobacco,  or  cubebs. 

There  are  two  other  arterial  dilators  in  common  use,  viz., 
potassium  iodide  and  chloral  hydrate.  They  do  not  show  any 
dilator  effect  in  normal  animals,  but  at  times  seem  to  have 
decided  effects  when  there  is  an  abnormally  high  blood-pressure. 
So  far  experiments  with  animals  have  not  taught  us  their  exact 
modus  operandi.     We  speak  of  these  drugs  again. 


Measures  for  Decreasing  the  Volume  of  the 
Blood 

Venesection. — Phlebotomy  or  blood-letting  is  the  process  of 
removing  blood  by  opening  a  vein.  A  large  vein,  usually  the 
median  basilic  or  median  cephalic,  is  exposed  and  surrounded 
by  two  ligatures,  the  proximal  one  of  which  is  tied.  A  light 
tourniquet  may  be  placed  about  the  upper  arm  to  increase  the 
venous  pressure.  The  vein  is  then  opened  distal  to  the  ligature, 
and  from  4  to  20  ounces  of  blood  allowed  to  flow,  after  which  the 
distal  end  of  the  exposed  vein  is  tied  off  by  the  remaining  liga- 
ture. If  there  is  much  venous  pressure,  a  funnel  or  tumbler  may 
be  held  above  the  vein  as  it  is  opened,  to  prevent  spurting  of  the 
blood.  As  phlebotomy  requires  the  tying  off  of  a  vein,  it  cannot 
be  repeated  many  times. 

Burton-Opitz  (1905)  showed  that  venesection  in  animals 
lowered  the  viscosity  of  the  blood  in  every  case,  but  Welsh  (19 12) 


232  PHARMACOLOGY   AND    THERAPEUTICS 

has  found  that  the  arterial  pressure  is  not  to  any  great  extent 
dependent  upon  the  viscosity  of  the  blood.  In  some  cases  after 
venesection  there  was  no  apparent  change  in  blood-pressure, 
though  the  viscosity  was  lessened.  In  other  cases  there  was  a 
rise  in  pressure,  accompanied  by  a  rise  in  viscosity,  or  a  rise  in 
pressure  with  a  fall  in  viscosity.  This  last  is  presumably  due 
to  hydremic  plethora  associated  with  the  disappearance  of 
edema.  In  the  author's  clinical  experience,  a  marked  and  pro- 
longed fall  in  pressure  has  usually  followed  venesection. 

Therapeutics. — 1.  In  conditions  of  high  venous  pressure,  as 
in  uremia  or  tricuspid  regurgitation  or  tricuspid  stenosis. 

2.  In  conditions  of  venous  accumulation  due  to  heart  weak- 
ness. 

3.  In  conditions  with  very  high  arterial  pressure,  as  in  uremia 
and  eclampsia,  to  decrease  the  volume  of  the  blood. 

4.  To  remove  poison — in  uremia,  in  eclampsia,  and  in  carbon 
monoxide  (illuminating  gas)  poisoning.  Its  value  in  removing 
poisons  is  problematic,  for  in  experiments  with  artificially  intro- 
duced toxins,  Levin  met  with  negative  results  by  this  method. 
In  carbon  monoxide  poisoning  the  poison  is  in  the  circulating 
blood,  so  it  is  advised  to  withdraw  about  15  to  30  ounces  of 
blood  and  replace  this  by  transfusion  of  fresh  blood. 

Venesection  for  the  removal  of  marked  local  congestion  is 
done  by  the  wet-cup  or  the  leech.  It  has  no  effect  on  general 
blood-pressure. 

Wet-cupping  is  a  process  by  which  blood  is  drawn  from  the 
part  by  suction  through  one  or  more  openings  in  the  skin.  These 
are  made  by  a  scalpel  or  by  a  special  scarificator  which  makes  6 
or  1 2  cuts  in  two  parallel  rows  ]  j  .    The  suction  is  created 

in  a  cupping-glass  or  small  tumbler  by  burning  cotton  in  it  or 
swabbing  it  inside  with  burning  alcohol  on  a  cotton  swab.  The 
mouth  of  the  glass  is  quickly  applied  to  the  skin,  and  as  the  heated 
air  cools,  it  creates  suction,  which  results  in  the  withdrawal  of 
serum  or  blood.  Cupping-glasses  may  also  be  had  with  rubber 
ball  or  syringe  attachment  for  creating  suction. 

Wet-cupping  is  but  little  used  today,  though  the  scars  are 
often  seen  in  older  patients.  Its  chief  uses  are — (a)  to  relieve 
edema  of  the  lungs,  the  cups  being  placed  on  the  chest- wall;  (b) 
to  overcome  suppression  of  urine,  the  cups  being  placed  over  the 
kidney  region. 

Dry-cupping — i.  e.,  cupping  without  an  incision  in  the  skin — 
produces  a  local  edema  or  congestion.  It  has  been  referred  to 
with  the  counterirritants. 

The  leech  (hirudo)  is  an  annelid  worm  with  a  sucker  at  each 
end  of  its  body.    At  its  mouth  end  there  are  three  teeth  ar- 


SHOCK  AND   COLLAPSE  233 

ranged  in  a  triradiate  manner,  so  that  its  bite  consists  of  three 
short  deep  gashes  radiating  from  a  common  center.  To  insure 
that  the  bite  shall  be  at  the  desired  spot,  the  leech  is  placed  inside 
a  glass  tube  or  over  a  hole  in  a  piece  of  paper,  the  mouth  of  the 
tube  or  the  hole  in  the  paper  being  placed  over  the  spot  to  be 
bitten.  If  the  leech  does  not  take  hold,  the  skin  may  be  pricked 
or  a  drop  of  blood  or  milk  placed  upon  it,  or  the  leech  may  be  put 
in  very  cold  water  for  a  minute  or  two  to  arouse  it. 

The  effect  of  the  leech  is  that  of  wet-cupping,  more  or  less 
blood  being  extracted.  As  the  mouth  of  the  leech  secretes  a 
substance  (hirudin)  which  prevents  the  coagulation  of  the  blood, 
the  bleeding  may  continue  for  a  long  time  after  the  animal  is 
removed.  Indeed,  it  may  be  necessary  to  employ  something  to 
stop  the  bleeding,  e.  g.,  adrenaline.  The  leech  may  be  removed 
easily  by  squeezing  its  head  or  by  placing  salt  upon  it.  The 
Swedish  leeches  are  considered  the  best,  as  they  extract  about 
half  an  ounce  of  blood,  while  the  American  leeches  extract  only 
1  or  2  drams. 

There  are  decided  disadvantages  in  the  use  of  leeches,  viz.: 

1.  They  may  not  be  clean;  in  any  case,  they  cannot  be  aseptic. 

2.  They  may  wander  and  get  into  one  of  the  body  orifices — e.  g., 
the  ear,  nose,  vagina,  etc.  3.  They  remove  an  uncertain  quan- 
tity of  blood. 

On  these  accounts  the  artificial  leech  is  sometimes  employed. 
It  consists  of  a  syringe  with  a  cup-like  nozzle  and  a  graduated 
barrel  with  which  slow  suction  is  made  over  a  cut  in  the  skin. 
It  is  merely  a  process  of  wet-cupping  with  a  graduated  syringe. 

Hirudin  is  employed  in  laboratory  work  to  prevent  coagula- 
tion of  the  blood,  the  small  amount  of  0.02  gm.  (-1  grain)  being 
sufficient  to  keep  1000  c.c.  of  blood  fluid  for  a  considerable  time. 
It  does  not  alter  the  viscosity  of  the  blood,  but  if  used  in  too 
large  quantities,  may  cause  agglutination  and  sedimentation  of 
the  corpuscles  (Bence). 

Shock  and  Collapse 

Following  severe  trauma  or  a  surgical  operation,  there  de- 
velops at  times  a  condition  of  pronounced  muscular  relaxation, 
with  rapid,  weak  heart,  low  blood-pressure,  and  depressed  respira- 
tion. There  is  a  similar  state  into  which  a  patient  may  pass  as 
the  result  of  severe  disease  or  loss  of  blood.  But  whether  the 
effects  when  produced  by  a  severe  infection  acting  steadily  for 
days  are  the  same  as  those  from  trauma,  or  are  produced  in  the 
same  manner,  are  questions  not  yet  decided.  And,  further, 
there  is  not  by  any  means  an  agreement  as  to  just  what  does 


234  PHARMACOLOGY  AND  THERAPEUTICS 

happen  in  a  patient  to  bring  him  into  the  state  described,  which 
is  known  as  shock  or  collapse.  There  is  a  tendency  on  the  part 
of  many  writers  to  use  the  term  "collapse"  when  the  prostra- 
tion results  from  toxic  causes,  as  disease  or  drugs,  or  from  loss 
of  blood,  and  to  confine  the  term  "shock"  to  the  condition 
developed  after  trauma,  either  accidental  or  operative.  But  the 
line  of  differentiation  between  the  two  cannot  be  satisfactorily 
drawn  at  the  present  time. 

The  two  most  striking  theories  as  to  the  cause  of  shock 
or  collapse  are  that  of  Crile  and  that  of  Yandell  Henderson. 
According  to  Henderson,  the  condition  is  due  to  lack  of  fluid  in 
the  circulatory  system.  He  argues  that,  as  the  result  of  pain, 
there  is  increased  respiration.  This,  or  fever,  or  acidosis,  or  the 
exposure  of  the  viscera  or  raw  tissues,  results  in  an  abnormal 
loss  of  COo  from  the  blood,  making  a  condition  known  as  acapnia. 
This  produces  a  lowering  of  the  osmotic  tension  of  the  blood  and 
increased  transudation  of  fluid  from  the  blood  into  the  tissues, 
so  that  the  total  volume  of  the  blood  falls.  The  venous  pres- 
sure is  so  low  that  the  heart  does  not  fill  well,  consequently  its 
output  is  decreased.  The  heart  is  smaller  than  normal,  and 
the  arteries  are  contracted.  The  condition  is  the  same  as  that 
after  hemorrhage  or  in  cholera. 

Crile 's  theory  is  that  shock  is  due  to  exhaustion  of  the  vaso- 
constrictor center  by  an  overwhelming  inflow  of  powerful  afferent 
impulses,  as  from  the  cut  nerves  of  a  severed  leg.  And  that 
collapse  results  from  a  functional  suspension  of  the  vasoconstrictor 
mechanisms,  owing  to  direct  or  reflex  depression  of  the  vaso- 
constrictor center,  heart  failure,  or  hemorrhage,  and,  in  addi- 
tion, according  to  Hill,  loss  of  reflex  tone,  which  allows  great 
relaxation  of  the  muscular  structures  of  the  body.  Not  all 
physiologists  agree  with  Crile  as  to  the  nature  of  shock  and 
collapse,  yet  if  a  distinction  between  exhaustion  of  the  centers 
and  functional  suspension  of  their  activities  can  be  made,  it  is 
one  of  great  importance  therapeutically;  for  while  in  the  latter 
case  the  use  of  stimulating  drugs  may  be  in  order,  yet  in  the 
former  stimulating  drugs  might  be  harmful,  and  the  main  indica- 
tion would  be  to  check  the  afferent  impulses  which  are  causing 
the  trouble. 

J.  M.  Wainwright's  experiments  (1906)  as  to  the  value  of 
spinal  analgesia  in  shock  lend  support  to  this  theory.  After 
artificial  traumatism,  designed  to  imitate  that  of  a  railway 
accident,  he  used  cocaine  and  stovaine  to  block  the  afferent 
impulses.     Two  series  of  his  experiments  are  of  interest,  viz. : 

1.  Dogs  completely  anesthetized  with  ether  had  their  hind 
limbs  kept  immersed  in  boiling  water.     Some  were  given  spinal 


SHOCK  AND   COLLAPSE  235 

anesthesia,  some  not.  Those  without  the  preliminary  spinal 
anesthesia  showed  a  short  rise  in  arterial  pressure  for  five  to  ten 
minutes,  then  a  rapid  fall  in  pressure,  and  death  in  twenty-five 
minutes  (average) .  In  the  dogs  with  spinal  anesthesia  there  was 
no  change  in  the  arterial  pressure  for  one  hour,  then  a  gradual 
fall  until  death,  presumably  as  the  cocaine  effect  was  wearing  off. 

2.  Dogs  were  completely  anesthetized  with  ether,  and  then 
had  their  hind  legs  crushed  to  a  pulp  by  repeated  blows  of  the 
blunt  side  of  an  ax.  After  twenty  minutes,  given  for  shock  to 
develop,  both  hind  legs  were  amputated  at  the  knee.  A  pre- 
liminary ligation  of  the  femoral  arteries  was  done  to  exclude  the 
effects  of  hemorrhage.  In  all  the  dogs  without  spinal  analgesia 
there  was  marked  shock,  and  2  out  of  7  dogs  died  during  or  imme- 
diately after  the  amputation.  The  dogs  which  had  a  spinal 
injection  before  the  amputation  were  all  in  good  condition  after 
the  amputation,  and  remained  so  until  the  cocaine  effect  had  worn 
off. 

Porter  states  that  the  vasoconstrictor  center  is  not  exhausted 
in  shock,  as  it  responds  in  the  usual  way  to  stimuli  through  sen- 
sory nerves.  But  in  well-developed  shock  the  center  is  evidently 
not  easily  influenced,  or  else  the  usual  pressor  influences  are 
changed  to  depressor.  (See  Strychnine.)  And  it  has  been 
suggested  that  in  shock  the  constrictor  synapses  are  easily 
paralyzed,  so  that  the  usual  vasoconstrictor  stimuli  become 
vasodilator. 

No  matter  what  the  underlying  factors  involved,  Hill  figures 
that  the  condition  of  shock  or  collapse  is  associated  with  cessa- 
tion of  the  reflexes  which  maintain  the  body  in  a  state  of  vascular 
tone  and  muscular  activity. 

Respiratory  paralysis  must  be  considered  with  collapse.  It 
may  be  due  to  direct  or  reflex  depression  of  the  center,  or  to  the 
failure  of  the  circulation  to  bring  the  center  sufficient  C02  for 
its  stimulation.  The  symptoms  are  those  of  asphyxia,  resulting 
in  death  unless  artificial  respiration  is  maintained.  If  the  heart 
action  remains  good,  artificial  respiration  may  often  be  continued 
until  the  center  regains  its  activity. 

The  Symptoms  and  Treatment  of  Collapse  and  Shock.— 
Whatever  the  cause  or  the  condition,  therapeutically  there  are 
about  three  distinct  degrees: 

1.  Mild  and  transitory  collapse  is  the  result  of  a  momentary 
suspension  of  the  cerebral  circulation,  as  a  reflex  effect  from 
sudden  emotional  or  psychic  influences,  or  from  a  drug  like  amyl 
nitrite  or  nitroglycerin,  or  from  momentary  ventricular  stoppage, 
as  in  heart-block.  It  is  probably  due  to  anemia  of  the  brain, 
caused  by  the  dilatation  of  the  splanchnic  arterioles,  and  this 


236  PHARMACOLOGY   AND    THERAPEUTICS 

dilatation  is  in  turn  the  result  of  a  failure  of  the  normal  sensory 
impulses  to  have  their  usual  effect  upon  the  vasoconstrictor 
center.  The  symptoms  are  fainting,  or  a  feeling  of  faintness. 
Treatment  is  directed  toward  favoring  the  blood-supply  of  the 
medulla.  If  the  patient  feels  faint,  he  may  sit  with  head  down 
between  the  legs  or  may  lie  down;  if  he  has  fainted,  he  should  be 
laid  with  head  lower  than  feet.  Ammonia  smelling-salts,  or  any 
rapidly  acting  strong  carminative,  such  as  aromatic  spirit  of 
ammonia  or  (hot)  whisky,  will  hasten  the  recovery. 

2.  A  moderate  degree  of  collapse  from  poisoning  manifests 
itself  by  the  gradual  onset  of  nausea,  and  perhaps  vomiting, 
diarrhea,  and  abdominal  weakness,  with  profuse  sweating, 
clammy  skin,  and  general  muscular  weakness  and  prostration 
(a  condition  experienced  by  many  embryo  smokers  after  their 
first  cigar). 

3.  Severe  collapse  may  be  gradual  in  its  onset  or  sudden.  It 
may  or  may  not  be  accompanied  by  unconsciousness.  The  face 
is  anxious,  or  if  the  patient  is  unconscious,  may  be  expressionless 
— mask-like.  The  skin  is  cold  and  clammy  and  bathed  in  per- 
spiration. It  is  usually  cyanotic,  but  is  pale  if  the  collapse  is 
due  to  hemorrhage  or  chloroform.  The  breathing  is  labored  and 
inefficient,  and  may  become  slow  and  shallow,  or  of  the  Cheyne- 
Stokes  type.  The  pulse  is  rapid  and  feeble,  perhaps  almost 
imperceptible.  The  temperature  falls,  and  may  reach  as  much  as 
three  or  four  degrees  below  normal.  The  mind  becomes  dulled, 
or  there  is  unconsciousness.  There  is  great  muscular  weakness 
with  prostration,  and  there  may  be  vomiting  and  convulsions. 

Treatment. — The  more  we  know  of  shock  and  collapse,  the 
less  we  pin  our  faith  to  drugs.  If  we  employ  them,  we  must  not 
let  the  stress  of  the  emergency  lead  us  into  giving  them  in  too 
large  doses.  In  such  an  emergency  we  have  seen  drugs  admin- 
istered in  amounts  that  might  have  proved  fatal  to  a  healthy 
person;  and  it  seemed  as  if  the  patient  might  have  died  from 
the  drugs  rather  than  from  the  collapse. 

There  is  one  drug  that  stands  preeminent  as  of  possible  value 
in  raising  the  arterial  pressure,  that  is,  adrenaline  (epinephrine). 
Its  action  is  peripheral,  therefore  takes  place  whether  the  vaso- 
constrictor center  is  paralyzed  or  not.  Unfortunately,  its  effects 
last  but  five  minutes  at  most.  It  may,  however,  be  added  to  a 
saline  infusion  and  administered  very  slowly  indeed ;  in  this  way 
its  action  may  be  obtained  for  perhaps  an  hour.  But  the  shock 
will  supervene  at  the  end  of  this  period. 

It  is  possible  that  a  few  doses  of  pituitrin  might  be  of  more 
use,  as  it  is  more  lasting,  but  its  repeated  administration  may 
result  eventually  in  vasodilatation  (Wiggers). 


SHOCK    AND    COLLAPSE  237 

Further  treatment  may  be : 

1.  Stimulants. — The  administration,  by  stomach  or  rectum, 
of  strong  hot  coffee.  The  hypodermatic  administration  of 
stimulants  to  the  central  nervous  system,  the  respiration,  and 
the  circulation,  such  as  atropine,  caffeine,  strychnine,  or 
digitalis,  according  to  the  several  indications,  and  of  arterial 
dilators  if  the  heart  itself  is  weak.  Intravenously,  the 
administration  of  -j-g-g-  grain  (0.5  mg.)  or  -^  grain  (1  mg.)  of 
strophanthin.  If  there  has  been  hemorrhage,  an  intravenous 
infusion  of  iooo  c.c.  of  normal  saline,  or  a  quart  of  hot  saline 
by  rectum. 

2.  The  administration  of  carbon]  dioxide  by  inhalation.  As 
this  gas  does  not  interfere  with  the  oxygen-carrying  power  of  the 
blood,  it  may  be  administered  with  oxygen.  It  stimulates  the 
respiratory  center,  tends  to  overcome  Cheyne-Stokes  or  shallow 
breathing,  and,  if  Henderson's  theory  is  correct,  tends  to  dispel 
the  condition  of  acapnia  which  is  the  cause  of  shock.  Henderson 
says  that  it  should  not  be  given  in  a  concentration  above  6  per 
cent. 

j.  A  position  to  favor  cerebral  blood-supply,  i.  e.,  with  the 
body  tilted  so  that  the  feet  are  higher  than  the  head.  The  legs 
may  even  be  raised  in  the  air  at  a  right  angle  to  the  body. 

4.  Mechanical  measures  to  raise  blood- pressure — the  limbs 
may  be  bandaged  from  fingers  to  shoulders,  or  Crile's  pneumatic 
jacket  applied,  or  weights  and  tight  binders  placed  over  the 
abdomen.  Meltzer  says  this  last  method  may  send  up  the  blood- 
pressure  and  hold  it. 

5.  Absolute  repose. 

6.  Maintenance  of  body  warmth  by  hot  blankets,  hot  towels, 
hot- water  bottles,. hot  drinks,  hot  enemata,  etc. 

7.  Plenty  of  air,  and,  if  necessary,  artificial  respiration  and 
the  inhalation  of  oxygen.  In  edema  of  lungs,  dry-cupping  and 
artificial  respiration  (Emerson),  especially  by  Meltzer's  intra- 
tracheal insufflation.      (See  under  General  Anesthetics.) 

The  treatment,  as  outlined,  may  need  to  be  modified  accord- 
ing to  the  cause  of  the  collapse.  For  example,  if  the  cause  is 
hemorrhage,  the  chief  end  of  the  medication  is  to  restore  the 
volume  of  the  blood;  if  the  cause  is  heart  failure,  it  may  be 
desirable  to  avoid  vasoconstriction,  i.  e.,  peripheral  resistance  and 
physical  work;  and  if  the  heart  failure  is  the  result  of  malnutri- 
tion from  failure  of  the  digestive  organs,  as  in  some  post-opera- 
tive cases,  transfusion  of  blood  maybe  indicated.  For  nutrition, 
Lazarus-Barlow  recommends  an  intravenous  of  2.25  per  cent,  of 
dextrose.     If  the  cause  is  a  blood-poison  like  carbon  monoxide 


238 


PHARMACOLOGY  AND    THERAPEUTICS 


(illuminating  gas),  transfusion  may  follow  a  preliminary  vene- 
section (Crile). 


REMEDIES  WHOSE  CHIEF  ACTION  IS  UPON  THE 
CENTRAL  NERVOUS  SYSTEM 

a.  The  stimulants. 

b.  The  depressants. 

Those    which    stimulate    the    central    nervous    system    are: 
caffeine,  strychnine,  atropine,  and  cocaine. 


Central  Nervous  Stimulants 
the  caffeine  group 

This  includes  the  three  alkaloids,  caffeine,  theobromine,  and 
theophylline,  caffeine  being  chemically  a  trimethyl  xanthine, 
and  the  other  two,  dimethyl  xanthines.  They  are  purin  bodies, 
are  closely  related  to  uric  acid,  and  are  but  feebly  basic,  i.  e., 
have  little  power  to  form  salts. 

There  are  three  classes  of  purins: 

i.  The  oxy purins,  which  include  hypoxanthine,  xanthine, 
and  uric  acid  (trioxypurin  or  oxyxan thine) . 

2.  The  amino  pur  ins,  which  include  adenin  and  guanin. 

3.  The  methyloxy purins,  which  include  this  caffeine  group. 


N 

I 
HC 


CH 


C— NH 

N  —  C— N^a 
Purin.  C6H4N4 


HN— CO 

I       I 
OC    C— N 


H 

\ 


CH 


I         II  y^ 

HN— C  — N^ 
Xanthine,  GH4N4O2 


HN— CO 


OC      C— N 


CH3 


HN— CO 

OC      C- 

I       II 
HN     C 


-NH 

\ 
CO 
-NH/ 


Uric  acid,  C6H4N403 
CH3 


CH3— N— CO 

I       I 
OC     C— N 


CH 


1        11         // 

CH3— N— C— N" 

Caffeine,  trimethyl 
xanthine. 


CH3— N— CO 

I       I 
OC    C— N/ 


H 


CH3— N  — C  — N  S 

Theobromine. 


CH 


CH3— N— C—  N^CH 
Theophylline. 


By  these  formulae  the  purin  nature  of  the  drugs  of  this  group 
is  evident,  as  also  their  close  relation  to  uric  acid. 


CAFFEINE  239 

CAFFEINE 

Trimethylxanthine,  or  caffeine,  is  a  feebly  basic  alkaloidal 
body  usually  prepared  from  damaged  tea-leaves.  It  is  found  in 
plants  growing  in  different  parts  of  the  world,  and  of  no  close 
botanic  relationship ;  and  the  finding  out,  by  the  inhabitants  of 
these  different  countries,  of  the  value  of  their  particular  plant  in 
making  a  stimulating  beverage,  and  of  the  best  way  of  preparing 
the  part  of  the  plant  used,  makes  an  interesting  story. 

In  Arabia  and  Egypt  the  beverage  was  made  from  coffee, 
the  roasted  seeds;  in  western  Africa,  from  kola,  the  dried  seeds; 
in  the  Amazon  region  of  South  America,  from  guarana,  a  brittle 
mass  made  by  pounding  up  the  seeds  to  a  paste  and  drying  by 
heat;  in  China  and  Japan,  from  tea,  the  fermented  leaves;  in 
Paraguay  and  Uruguay,  from  mate  or  Paraguay  tea,  the  dried 
leaves  and  shoots  of  a  species  of  Ilex  or  holly.  The  Appalache 
tea  (Ilex  cassine),  which  grows  from  Virginia  to  the  Gulf  of 
Mexico,  contains  0.12  percent,  of  caffeine  and  2.4  per  cent,  of 
tannin  (Blyth,  1909).  Having  no  caffeine  plants,  the  inhabi- 
tants of  Mexico  and  the  West  Indies  made  their  stimulating 
beverage  of  the  fermented  seeds  of  the  chocolate  plant,  which 
contain  the  close  relative,  theobromine.  Mate  contains  about 
1.3  per  cent,  of  the  alkaloid,  tea,  1  to  4  per  cent.,  coffee,  0.6  to 
2  per  cent.,  kola,  1  to  2  per  cent.,  and  guarana,  3  to  6  per  cent. 

Preparations  and  Doses. — Caffeine  (caffeina)  is  soluble  in 
46  parts  of  water  and  54  of  alcohol.     Dose,  1  grain  (0.06  gm.). 

Citrated  caffeine  (caffeina  citrata)  is  a  mixture  of  equal  parts 
of  caffeine  and  citric  acid.  On  account  of  the  feebly  alkaloidal 
nature  of  caffeine,  the  citric  acid  is  added  in  excess.  It  is  soluble 
in  25  parts  of  water.  Dose,  2  grains  (0.13  gm.).  This  is  the 
favorite  preparation. 

Effervescent  citrated  caffeine  (caffeina  citrata  effervescens)  is  a 
granular  salt  which  contains  4  per  cent,  of  citrated  caffeine,  i.  e., 
2  per  cent,  of  caffeine,  with  citric  and  tartaric  acids  and  sodium 
bicarbonate  to  make  it  effervesce  when  added  to  water.  Dose, 
50  grains  (about  two  teaspoonfuls). 

Compound  acetanilid  powder  (pulvis  acetanilidi  compositus) 
contains  10  per  cent,  of  caffeine,  70  per  cent,  of  acetanilid,  and 
20  per  cent,  of  sodium  bicarbonate,  but  is  essentially  an  acetanilid 
preparation. 

Guarana  is  official,  and  is  assayed  to  contain  not  less  than 
3.5  per  cent,  of  alkaloid.  It  contains  much  tannic  acid.  It  has 
one  official  preparation,  the  fluidextract,  dose,  30  minims  (2  c.c). 

Caffeine  and  sodium  benzoate  and  caffeine  and  sodium  salicylate 
are  unofficial  double  salts  which  are  soluble  in  twice  their  weight 
of  water,  and  can  be  used  hypodermatically.     Dose,  2  grains 


240  PHARMACOLOGY  AND  THERAPEUTICS 

(0.13  gm.).  The  salicylate  contains  about  60  per  cent,  and  the 
benzoate  about  50  per  cent,  of  caffeine. 

Pharmacologic  Action. — Alimentary  Tract. — The  taste  is  bit- 
ter.    There  is  no  direct  action  upon  the  tissues. 

Absorption  is  fairly  rapid  from  the  stomach  and  intestines. 
Cerebral  stimulation  from  stomach  doses  is  evident  in  from  one- 
half  to  one  and  one-half  hours. 

Nervous  System. — Coffee  and  tea  are  so  much  used  as  bever- 
ages that  their  stimulating  and  nervous  effects  are  well  known  to 
the  laity.  These  effects  are  of  importance,  not  only  in  the 
medicinal  use  of  the  drug,  but  also  because  of  overindulgence 
in  the  beverages. 

Cerebrum. — After  a  fair  dose  of  caffeine  the  mind  becomes 
more  alert,  the  attention  keener,  and  the  spirits  brighter;  or  a 
state  of  drowsiness  and  inattention  will  be  changed  to  one  of 
wakefulness  and  brightness  and  activity.  In  other  words, 
there  is  a  real  stimulation  of  the  intellectual  functions,  especially 
those  of  reason,  judgment,  will,  and  self-control,  the  highest 
functions  of  the  mind.  At  the  same  time,  the  perceptions  are 
more  acute,  the  appreciation  of  pain  is  heightened,  and,  as  shown 
by  the  esthesiometer,  the  sense  of  touch  is  more  discriminating. 
Kraepelin  found  that  the  reception  of  sensory  impulses  and  the 
association  of  ideas  are  facilitated,  but  the  transmission  of 
thought  into  action  is  retarded.  This  is  because  of  the  inter- 
vention of  judgment.  Caffeine  also  stimulates  the  motor  areas 
of  the  brain,  as  indicated  in  a  dog  by  the  greater  motor  response 
to  a  given  electric  stimulus  of  the  exposed  motor  area,  and  as 
shown  in  man  by  increased  activity  of  voluntary  motion.  So 
caffeine  is  a  true  stimulant  of  the  intellectual  and  motor  centers 
of  the  cerebrum.  It  is  directly  antagonistic,  in  its  cerebral  effects, 
to  alcohol. 

Hollingworth,  in  his  laboratory  of  psychology,  at  Columbia, 
experimented  on  6  assistants  and  16  students  for  a  period  of 
forty  days.  He  used  capsules  of  citrated  caffeine,  with  capsules 
of  sugar  of  milk  as  controls.  None  of  the  subjects  knew  which  of 
these  was  being  taken.  He  made  76,000  measurements  and  800 
efficiency  curves,  with  and  without  caffeine.  Of  the  citrated 
caffeine,  which  is  of  50  per  cent,  strength,  1  to  4  grains  produced 
slight  nervousness,  not  noticeable  until  several  hours  after  the 
dose.  There  were  increased  speed  and  accuracy  of  movement, 
beginning  in  about  an  hour  and  lasting  about  four  hours.  Six 
grains  produced  marked  unsteadiness. 

In  typewriting,  small  doses  increased,  and  doses  above  three 
grains  retarded,  the  speed;  but  the  quality  of  the  work,  even 
with  the  larger  doses,  was  superior  to  that  of  the  same  subjects 


CAFFEINE  241 

on  control  days.     There  was  no  fatigue  reaction  to  the  extra 
work. 

In  calculations,  there  was  marked  increase  in  ability,  the 
stimulation  beginning  in  about  one  hour  and  lasting  several 
hours.  The  morning  following  the  experiment  showed  without 
exception  a  clear  improvement  over  the  work  of  the  morning 
preceding  the  experiment. 

In  sick  people,  the  condition  of  wakefulness  and  keener  per- 
ception brought  about  by  caffeine  is  usually  highly  undesirable; 
and  in  habitual  insomnia  one  of  the  first  things  to  look  out  for 
is  that  the  patient  shall  not  take  tea  or  coffee  toward  evening. 

Medulla. — Caffeine  strongly  stimulates  the  respiratory  center, 
and  moderately  the  vasoconstrictor  and  the  vagus  centers. 

Spinal  Cord. — Caffeine  stimulates  the  motor  cells  and  pro- 
motes the  passage  of  impulses  through  the  spinal  cord  in  the  same 
manner  as  strychnine,  but  to  a  much  smaller  degree.  (See 
Strychnine  for  more  detailed  study  of  this  property.)  It,  there- 
fore, increases  reflex  activity,  and  tends  to  improve  the  "tone" 
of  muscle;  and  in  marked  amounts  may  cause  twitching  of  the 
limb  and  face  muscles.  In  the  laboratory  it  is  often  noticed  that 
an  animal  lightly  anesthetized  with  ether  or  chloroform  will 
become  conscious  and  recover  his  reflexes  if  a  hypodermic  of 
caffeine  is  administered. 

Muscle. — If  the  gastrocnemius  of  a  curarized  frog  is  painted 
with  a  weak  solution  of  caffeine,  or  if  caffeine  is  injected  into  its 
supplying  artery,  the  muscle  will  contract  more  promptly  and  to 
a  smaller  stimulus,  and  will  lift  a  heavier  load,  i.  e.,  its  irritability 
and  its  strength  are  increased  by  the  direct  action  of  the  drug. 
The  total  work  of  the  muscle  before  fatigue  sets  in  is  also  in- 
creased. Such  direct  stimulation  occurs  in  both  striated  and 
cardiac  muscle,  but  not  to  any  great  extent,  if  at  all,  in  smooth 
muscle,  though  the  latter  may  be  improved  in  tone  (Sollmann 
says  that  smooth  muscle  is  stimulated).  From  overdoses  the 
typical  phenomena  of  fatigue  come  on  early,  the  muscle  being 
poisoned.  In  frogs,  large  doses  induce  a  stiffening  of  the  muscle 
like  that  of  rigor  mortis;  in  mammals  this  effect  is  not  seen,  as 
death  takes  place  before  this  stage  is  reached. 

Power  and  Endurance. — Human  experiments  with  the  ergo- 
graph  show  greater  power  and  greater  endurance  of  the  finger 
muscles.  In  comparative  experiments  with  whole  companies  of 
soldiers  on  the  march  under  like  conditions,  Leistenstorfer,  for 
the  German  government,  found  that  when  the  soldiers  were  well 
supplied  with  food,  those  that  were  given  tea  or  coffee  could 
endure  more  prolonged  and  more  severe  marches  than  those  that 
did  not  get  tea  or  coffee.  If  no  food  was  supplied,  fatigue 
16 


242  PHARMACOLOGY  AND  THERAPEUTICS 

appeared  first  in  the  tea-  and  coffee-drinkers.  That  is  to  say, 
tea  and  coffee  increased  the  power  for  continuous  physical  work 
so  long  as  the  supply  of  nutritive  material  was  ample,  but  caused 
early  exhaustion  when  food  was  withheld. 

Caffeine,  thus,  may  act  to  increase  the  capacity  for  work  in 
several  ways,  viz.:  i.  By  increasing  mental  vigor.  2.  By 
stimulating  the  motor  areas  of  the  brain  and  so  increasing  the 
range  and  control  of  voluntary  acts.  3.  By  increasing  the  motor 
activity  of  the  cord  and  so  improving  the  tone  of  muscle.  4.  By 
directly  stimulating  the  voluntary  muscles  themselves. 

Circulatory  System. — In  the  isolated  heart,  the  beats  under 
caffeine  are  increased  in  frequency  and  are  stronger,  i.  e.,  the 
heart  will  contract  against  a  greater  aortic  pressure.  As  this  is 
the  result  whether  the  vagus  and  accelerator  endings  have  been 
paralyzed  or  not,  it  must  be  due  to  direct  stimulation  of  the 
heart  muscle.  In  the  intact  mammal,  after  a  good-sized  dose, 
the  rate  is  not  much  accelerated  and  may  even  be  slowed,  the 
effect  being  the  resultant  of  a  mild  stimulation  of  the  vagus 
center  and  mild  stimulation  of  the  muscle.  Repeated  medicinal 
doses,  like  the  habitual  drinks  of  tea  and  coffee,  have,  as  a  rule, 
little  if  any  effect  on  the  rate,  the  force,  and  the  output  of  the 
heart. 

In  some  cases  the  heart  muscle  stimulation  is  pronounced 
after  a  single  dose  or  a  cup  or  two  of  coffee;  and  it  is  possible  that 
in  these  cases  the  increased  heart  action  is  largely  due  to  increased 
flow  through  the  coronary  arteries.  But  sometimes  the  only 
results  in  human  sickness  are  nervousness,  wakefulness,  cardiac 
discomfort,  and  palpitation.  Pilcher  says  that  in  shock  the 
danger  of  cardiac  death  is  increased  by  caffeine. 

Enormous  doses  bring  about  depression  of  the  heart  muscle 
with  slowing,  and  partial  heart-block  has  been  reported  in  ani- 
mals. But  the  author  has  some  clinical  evidence  that  caffeine 
opposes  the  good  action  of  digitalis  in  impairing  conduction  in 
cases  with  auricular  fibrillation;  and  in  cold-blooded  animals, 
C.  C.  Lieb  has  repeatedly,  with  caffeine,  removed  a  heart -block 
that  had  been  produced  with  cocaine. 

Arteries. — The  vasoconstrictor  center  is  moderately  stimu- 
lated, so  that  the  arteries  may  contract  and  raise  arterial  pres- 
sure. Sollmann  (1910)  says  that  there  is  a  general  peripheral 
vasodilator  action  that  overcomes  the  effect  of  stimulation  of 
the  vasoconstrictor  center.  A  hypodermic  injection  of  5  grains 
(0.3  gm.)  of  the  citrated  caffeine,  or  of  the  caffeine  and  sodium 
benzoate,  has  usually  resulted  in  a  slight  slowing  of  the  pulse 
with  no  measurable  effect  on  arterial  pressure.  Rarely  the 
pressure  rises  as  much  as  10  mm.  of  mercury.     Whether  or  not 


Aur. 


Ven. 


B.  P. 


Fig.  31. — Caffeine,  5  mg.  per  kilo,  resulted  in  increased  contractility  of  auricle 
and  ventricle  (down-stroke),  and  a  rise  in  blood-pressure  from  68  to  82  mm.  The 
effect  was  somewhat  lasting.  Chloroform,  10  breaths,  diminished  the  contractility 
of  both  auricle  and  ventricle,  and  caused  a  fall  in  blood-pressure  from  76  to  56  mm. 
(Tracing  made  by  Dr.  C.  C.  Lieb.) 


CAFFEINE  243 

it  would  have  greater  power  than  this  to  bring  a  low  blood-pres- 
sure to  normal  is  problematic.  At  the  same  time  this  dose  of 
5  grains  sometimes  induces  undesirable  nervous  effects,  and 
cannot  be  repeated  at  very  close  intervals  without  risk  of  over- 
stimulation of  the  cerebrum  and  spinal  cord. 

Whether  or  not  Sollmann's  finding  that  the  systemic  arteries 
are  dilated  by  a  peripheral  action  can  apply  to  small  doses  in 
human  beings  remains  to  be  proved;  but  in  any  case  caffeine 
never  constricts  the  arteries  that  are  not  under  the  control  of 
the  vasoconstrictor  center,  viz.,  those  of  the  lungs,  the  cerebrum, 
and  the  heart.  In  experimental  work  the  coronary  arteries  are 
regularly  dilated,  and  this  may  be  an  important  factor  in  the 
emergency  stimulation  of  the  heart.  Cushny  suggests  that  it 
may  be  secondary  to  the  direct  cardiac  stimulation.  The 
arteries  of  the  kidneys  are  also  dilated. 

Caffeine  as  a  circulatory  stimulant  is,  therefore,  purely  an 
emergency  drug,  and  not  one  to  be  used  repeatedly.  It  can  in 
no  sense  do  the  work  of  digitalis.  We  are  inclined  to  think  that 
much  of  its  apparent  value  in  conditions  of  low  blood-pressure 
is  due,  not  to  circulatory  stimulation,  but  to  stimulation  of  the 
central  nervous  system,  the  brain,  cord,  and  respiratory  center, 
the  improvement  in  muscular  tone  and  respiratory  and  mental 
vigor  being  important  in  conditions  of  general  weakness. 

Respiratory  System. — Caffeine  is  a  stimulant  of  the  respiratory 
center,  the  inspirations  being  increased  in  both  depth  and  fre- 
quency. In  the  laboratory  this  stimulation  is  best  seen  after 
the  center  has  been  depressed  by  narcotic  drugs,  such  as  mor- 
phine. Toxic  doses  may  induce  oppressive  breathing  from  excess- 
ive action  of  the  respiratory  muscles,  and  eventually  exhaust 
the  center,  causing  asphyxia  and  death. 

Metabolism  is  increased  by  large  doses,  with  a  slight  rise  in 
temperature.  From  ordinary  amounts  of  coffee  or  tea  there  is 
no  essential  effect.  Magnus  measured  the  oxygen  intake  during 
one-hour  periods  for  three  hours  after  the  administration  of 
coffee.  After  15  grams  of  coffee  (amount  for  about  two  cups) 
made  into  a  beverage,  there  was  from  3  to  6  per  cent,  decrease 
in  oxygen  intake;  after  20  grams  there  was  from  1  to  4  per  cent, 
increase,  and  after  25  grams,  from  6  to  n  per  cent,  increase,  this 
last  being  associated  with  greater  motor  and  reflex  activity  and 
stronger  pulse. 

Excretion  is  fairly  rapid.  Caffeine  tends  to  lose  its  methyl 
groups  as  it  passes  through  the  body,  with  the  formation  of 
dimethyl  and  monomethyl  xanthines,  xanthine,  and  urea;  and 
these,  with  perhaps  some  unchanged  caffeine,  are  excreted  in 
the  urine.     According  to  most  investigators  there  is  no  increase 


244  PHARMACOLOGY  AND  THERAPEUTICS 

in  the  excretion  of  uric  acid  in  health;  but  Schittenhelm  (1910) 
says  it  is  increased.  In  chronic  gout  Hess  and  Schmoll,  and  also 
Strauss,  have  determined  that  both  caffeine  and  theobromine 
increase  the  uric  acid.  In  Strauss'  case  with  gout  in  fingers  and 
knees,  a  diet  of  2  liters  of  milk,  300  gm.  of  bread,  and  40  gm.  of 
butter  gave  an  average  uric-acid  excretion  of  0.363  gm.  per  day. 
On  the  addition  of  2  gm.  caffeine  (a  very  large  amount)  to  the 
day's  dietary  the  uric  acid  rose  to  0.621  gm. 

Kidneys. — Caffeine  is  a  drug  frequently  employed  in  the 
physiologic  investigation  of  the  kidneys,  and  these  investigations 
have  at  the  same  time  enlarged  our  knowledge  of  the  pharma- 
cology of  caffeine.  It  is  strongly  diuretic,  producing  diuresis  in 
the  isolated  kidney  just  as  well  as  in  the  intact  animal,  and  in  the 
latter  whether  general  blood-pressure  is  raised  or  not ;  its  diuresis 
is  therefore  not  due  to  changes  in  the  general  circulation.  More- 
over, local  dilatation  of  the  arterioles  is  not  the  essential  factor, 
though  usually,  as  measured  in  an  oncometer,  the  kidney  is 
enlarged  during  the  diuresis  and  the  arterioles  are  dilated.  For 
diuresis  goes  on  even  if  the  kidney  is  incased  in  a  plaster  cast  so 
that  it  cannot  expand;  and  there  are  cases  in  which,  even  when 
it  dilates  the  arterioles,  caffeine  produces  no  diuresis. 

To  compare  urine  with  the  blood  from  which  it  is  derived,  a 
solution  of  the  dialyzable  substances  of  the  blood  in  the  propor- 
tions in  which  they  occur  in  the  blood  is  filtered  through  an  animal 
membrane,  and  the  filtrate  diluted  with  distilled  water  until  it  has 
the  same  content  of  urea  as  the  urine.  In  this  fluid  it  is  found 
that  the  proportion  of  sulphate  and  phosphate  is  somewhat  more 
than  in  the  urine,  and  the  proportion  of  sodium  chloride  is  con- 
siderably more  (Loewi).  This  points  to  a  difference  in  the  de- 
gree of  reabsorption  of  the  different  salts  by  the  kidney  tubules, 
the  chloride  being  reabsorbed  readily,  the  sulphate  and  phos- 
phate with  more  difficulty,  and  the  urea  with  the  greatest  diffi- 
culty of  all.  In  caffeine  diuresis  Loewi  finds  that  the  more 
active  it  is,  the  more  nearly  does  the  proportion  of  chlorides  to 
urea  in  the  urine  approach  their  proportion  in  the  blood,  a  condi- 
tion that  might  be  expected  if  the  glomerular  fluid  fails  to  be 
subjected  to  the  normal  resorption  as  it  passes  through  the 
tubules.  It  would  seem,  then,  that  caffeine  may  perform  part 
of  its  action  as  a  diuretic  by  lessening  the  reabsorptive  power  of 
the  tubule  cells,  though  it  may  be  that  reabsorption  fails  to  take 
place  merely  as  the  result  of  the  increased  secretory  activity  of 
the  tubule  cells. 

Pearce,  in  his  studies  of  experimental  acute  nephritis,  found 
that  in  tubular  nephritis  caffeine  may  cause  dilatation  of  the 
renal  vessels,  so  that  the  kidney  volume  is  increased  as  much  as 


CAFFEINE 


245 


in  a  normal  kidney,  yet  without  producing  diuresis.  And  in  one 
of  his  experimental  animals  caffeine  caused  abundant  diuresis 
without  producing  any  increase  in  the  volume  of  the  kidney,  i.  e., 
without  dilatation  of  the  vessels.  In  uranium  nephritis  there 
was  a  stage  in  which  caffeine,  sodium  chloride,  sodium  sulphate, 
urea,  and  dextrose  all  produced  vascular  dilatation,  yet  caffeine 


Fig.  32. — Normal  dos:  I,  Drops  of  urine.  II,  Kidney  volume.  Ill,  General 
arterial  pressure:  a,  Before  caffeine;  b,  fourteen  minutes  after  caffeine  (from 
Pearce,  Hill,  and  Eisenbrey). 

was  the  only  one  that  produced  diuresis.  His  inference  was  that 
the  diuresis  resulted  from  stimulation  of  the  tubule  cells,  which 
are  not  affected  by  the  other  substances. 

These  experiments,  with  many  others  of  a  like  nature,  seem 
to  indicate  that  the  diuresis  of  caffeine  is  not  at  all  through  a 
circulatory  action,  but  is  due  to  a  direct  action  of  the  caffeine 
on  the  cells  of  the  renal  tubules.     (See  also  under  Diuretics.) 


246 


PHARMACOLOGY  AND  THERAPEUTICS 


But  whether  the  action  is  stimulation  of  the  tubule  cells  or  interfer- 
ence with  reabsorption,  or  both,  has  not  been  finally  determined. 
Overdoses  cause  no  harm  to  the  kidney,  but  from  continued  use, 
as  in  coffee-  and  tea-drinking,  the  diuretic  power  becomes  less. 
In  caffeine  diuresis  there  is  increased  excretion  of  certain  sub- 


Fig-  33- — Dog  after  vascular  nephritis  produced  by  arsenic:  a,  Before  caffeine; 
b,  eight  minutes  after  caffeine;  c,  twenty-two  minutes  after  caffeine.  I,  Drops 
of  urine.  II,  Volume  of  kidney.  Ill,  General  arterial  pressure  (from  Pearce, 
Hill,  and  Eisenbrey). 


stances  that  are  known  to  be  excreted  by  the  tubule  cells,  as 
urinary  pigment  and  creatin.  Salant  and  Ringer  (191 2)  find 
the  latter  increased  100  per  cent,  or  more  in  rabbits. 

As  with  other  diuretics,  the  more  water  there  is  in  the  body, 
the  more  readily  is  diuresis  produced.  V.  E.  Henderson  has 
shown  that  when  the  body  is  poor  in  water,  caffeine  fails  as  an 
excitant  to  secretion,  though  it  brings  about  the  usual  dilatation 


CAFFEINE 


247 


of  the  renal  arterioles.  But  caffeine  is  strongly  diuretic,  for 
Rafael  found  that  7^  grains  of  caffeine  with  1000  c.c.  of  water 
in  a  day  increased  his  urine  42  per  cent,  over  that  from  1000  c.c. 
of  water  without  the  caffeine. 

It  is  of  interest  that  caffeine  increases  peristalsis  in  the  ureters, 
for  this  alone  during  a  short  experimental  period  may  favor  the 
urine  flow. 

Toxicology.— As  coffee  and  tea  are  employed  so  extensively 
as  beverages,  mild  caffeine  poisoning  is  usually  seen  from  the  use 
of  these,  rather  than  from  the  medicinal  use  of  caffeine. 

Acute  Poisoning. — (a)  When  a  moderate  overdose  of  caffeine 
is  taken,  as  two  or  three  times  the  accustomed  amount  of  coffee 
or  tea,  the  brain  and  cord  become  overactive,  and  there  are 
increased  reflex  irritability,  increased  motor  activity,  and  impair- 
ment of  the  mental  power  because  ideas  follow  one  another  so 
rapidly  as  to  prevent  concentration  of  thought.  The  patient 
cannot  concentrate  his  attention,  and  is  excitable,  restless,  and 
unable  to  sit  quietly.  His  arm  and  leg  muscles  or  face  muscles 
may  twitch,  and  he  may  feel  gastric  discomfort,  with  oppression 
about  the  heart  and  palpitation.  His  breathing  may  be  deep, 
but  oppressive. 

The  treatment  consists  of  rest,  with  bromides  or  other  central 
sedatives.  Sollmann  and  Pilcher  found  that  alcohol  increased 
the  toxicity  of  poisonous  amounts  of  caffeine,  though  caffeine 
does  not  increase  the  toxicity  of  alcohol. 

(b)  With  marked  toxic  doses  there  may  be  vomiting,  convul- 
sions, weak  and  irregular  heart,  low  arterial  pressure,  and  col- 
lapse. Death  takes  place  usually  from  failure  of  the  heart 
muscle,  but  may  be  due  to  exhaustion  of  the  respiratory  center. 
One  case  of  death  was  reported  by  Allard  in  1904,  and  the  author 
has  seen  two  probable  instances  in  cardiac  cases.  One  of  our 
own  students  took  two  teaspoonfuls  of  pure  citrated  caffeine 
instead  of  effervescing  citrated  caffeine.  He  went  into  collapse 
and  later  vomited  several  times.  He  was  very  anxious  and 
nervous,  and  his  heart  remained  weak  and  irritable,  so  that  he 
could  not  leave  his  bed  for  seventeen  days.  He  continued  to  be 
excessively  nervous,  and  suffered  from  insomnia  for  many  months. 

The  treatment  of  severe  poisoning  is  that  for  collapse.  Espe- 
cially necessary  is  absolute  repose.  Because  of  the  exhaustion  of 
the  centers,  drugs  are  contraindicated.  Saline  irrigations  may 
be  of  use  to  promote  elimination  by  the  kidneys. 

Therapeutics. — 1.  To  counteract  the  depression  of  the  re- 
spiratory, cerebral,  and  spinal  centers,  and  the  loss  of  tone  of  the 
muscles  in  collapse,  especially  that  resulting  from  narcotic  drugs, 
as  chloral,  morphine,  alcohol,  or  ether. 


248  PHARMACOLOGY  AND   THERAPEUTICS 

2.  As  a  stimulant  or  ionic  in  convalescence  from  acute  dis- 
ease, as  after  influenza  or  pneumonia,  in  nervous  exhaustion,  in 
conditions  of  mental  and  physical  weariness,  and  in  depressed 
states  of  the  mind. 

2).  As  a  diuretic  in  dropsy,  or  in  any  condition  in  which  in- 
creased urination  is  desired.  In  inflammatory  conditions  of  the 
kidneys  the  effect  depends  upon  the  amount  of  kidney  tissue  that 
is  still  functional. 

4.  Perhaps  as  an  emergency  heart  stimulant. 

It  is  frequently  given  with  drugs  like  acetanilid  and  phenac- 
etin,  because  of  an  erroneous  idea  that  it  will  prevent  the  depres- 
sion that  these  sometimes  cause.  But  the  studies  of  Hale  in  the 
laboratory  of  Public  Health  and  Hygiene  at  Washington  have 
shown  that  the  toxicity  of  acetanilid  and  antipyrine  are  increased 
by  caffeine.  As  a  matter  of  fact,  many  of  the  cases  of  acute 
acetanilid  poisoning  have  occurred  from  mixtures  which  con- 
tained caffeine.     (See  Antipyretics.) 

In  the  employment  of  caffeine  in  therapeutics,  three  things 
must  always  be  borne  in  mind,  viz.:  (1)  It  strongly  stimulates 
the  cerebral  cortex,  so  that  a  few  doses  may  result  in  an  excitable 
nervous  condition,  with  alert  mind  and  complete  inability  to 
sleep,  at  a  time  when  an  inactive  mind  and  sleep  may  be  the 
greatest  necessities  of  the  patient.  What  Mackenzie  says  of  the 
treatment  of  heart  disease  is  especially  to  be  noted,  viz.:  "What- 
ever the  form  the  heart  failure  may  assume,  sleep  is  essential. 
It  may  be  taken  as  an  axiom  that  if  the  patient  does  not  get 
sufficient  sleep  he  will  never  get  well."  (2)  It  stimulates  the 
perceptions,  and  so  may  increase  a  patient's  suffering  and  the 
appreciation  of  his  sick  condition;  in  very  sick  patients  a  condi- 
tion of  apathy  is  better.  (3)  Its  dose  is  uncertain,  as  there  is  a 
great  difference  in  individual  susceptibility  to  the  drug,  and  the 
tea  and  coffee  habits  establish  varying  degrees  of  tolerance.  It 
is  a  well-known  fact  that  one  person  will  sleep  well  and  experi- 
ence no  discomfort  after  several  cups  of  tea  or  coffee,  while 
another  may  be  kept  awake  or  have  palpitation  of  the  heart  from 
one  cup.  A  cup  of  coffee  contains  from  1  to  2  grains  of  caffeine; 
therefore  5  grains  of  citrated  caffeine  every  four  hours,  as  I  have 
seen  prescribed,  would  equal  a  cup  of  strong  coffee  every  four 
hours,  all  day  and  perhaps  for  several  days.  This  would  be  a 
large  amount  for  one  who  is  healthy,  even  if  not  especially  sus- 
ceptible to  caffeine;  and  it  is  a  poisonous  quantity  for  one  who  is 
sick  and  is  susceptible.  Powerful  remedies  to  which  persons 
show  marked  variations  in  susceptibility  should  have  very  little 
employment  in  medicine,  because  one  cannot  calculate  in  ad- 
vance the  probable  dose  that  will  give  the  desired  effect.     More- 


THEOBROMINE  AND  CAFFEINE  BEVERAGES        249 

over,  tea  and  coffee  are  so  much  used  that  caffeine  has  often  lost 
its  influence  to  a  greater  or  less  degree.  These  three  things, 
then,  must  be  remembered: 

1.  Caffeine  promotes  wakefulness  and  nervousness. 

2.  It  increases  the  perceptions. 

3.  Its  dose  is  uncertain,  because  of  marked  variations  in 
individual  susceptibility. 

Administration. — Ordinarily,  coffee  or  tea  may  be  employed, 
or  the  citrated  caffeine  given  in  one-grain  tablet  triturates.  In 
collapse,  hot  strong  coffee  may  be  given  by  mouth  or  by  rectum; 
or  the  salicylate  or  benzoate  of  sodium  with  caffeine  may  be 
given  hypodermatically. 

CAFFEINE  ALLIES 

Theobromine,  occurring  in  chocolate  to  the  extent  of  0.3  to 
2  per  cent.,  and  theophylline,  which  occurs  in  minute  quantities 
in  tea-leaves,  but  is  manufactured  synthetically  for  the  market, 
are  isomeric  dimethylxanthines. 

Theobromine  stimulates  both  cardiac  and  voluntary  muscles 
to  some  extent,  and  has  the  diuretic  power  of  caffeine.  But  it  is 
preferred  as  a  diuretic  because  it  lacks  the  undesirable  central 
effects.  For,  having  no  vasoconstrictor  action  and  but  little 
stimulating  effect  upon  the  brain,  it  may  be  given  in  much  larger 
doses  without  the  production  of  wakefulness.  The  dose  is 
10  grains  (0.6  gm.),  given  in  capsule  or  powder  three  or  four 
times  a  day.  As  it  is  insoluble  and  but  slowly  absorbed,  its 
soluble  combination  with  sodium  salicylate,  known  as  diuretin, 
or  that  with  sodium  acetate,  known  as  agurin,  may  be  preferred. 
Their  dose  is  20  grains  (1.3  gm.).  They  are  not  official.  We 
have  many  times  noted  a  very  great  rise  in  the  urine  flow  of 
dropsical  patients  after  theobromine  or  diuretin. 

Theophylline  (theocine)  has  the  same  action  and  dose,  but  it 
is  more  irritating  to  the  stomach,  so  that  nausea  is  not  infrequent, 
and  it  has  some  of  the  central  effects  of  caffeine  (Thomas). 
Theocin-acet-sodium  is  a  soluble  salt  of  this  alkaloid. 

THEOBROMINE  AND  CAFFEINE  BEVERAGES 

The  ones  that  are  in  more  or  less  universal  use  among  civilized 
people  are  coffee,  tea,  and  chocolate.  Most  of  our  coffee  comes 
from  Brazil,  our  tea  from  Japan,  China,  and  India,  and  our 
chocolate  from  the  West  Indies.  The  use  of  caffeine-bearing 
parts  of  plants  as  beverages  in  various  parts  of  the  world  has 
already  been  spoken  of.  The  dried  coffee-seeds  are  roasted  and 
then  ground  before  use.  Roasted  coffee  contains  0.6  to  2  per 
cent,  of  caffeine,  a  small  amount  of  caffeol  (caffeon),  and  a  large 


250  PHARMACOLOGY  AND  THERAPEUTICS 

amount  of  tannic  acid.  Caffeol  is  an  empyreumatic  volatile  oil 
(a  mixture)  developed  in  the  roasting.  It  is  the  source  of  the 
flavor  and  aroma  of  the  coffee,  and  is  so  penetrating  that  a 
single  drop  of  it  will  fill  a  room  with  the  coffee  odor.  The  tannic 
acid  of  coffee,  caffeotannic  acid,  unlike  that  of  tea,  does  not 
precipitate  albumin,  gelatin,  or  alkaloids,  and  is  not  astringent. 
It  is  consequently  of  no  use  as  a  precipitant  in  poisoning  by  alka- 
loids. It  constitutes  undesirable  extractive  matter,  however, 
in  coffee,  for  so  much  colloid  matter  tends  to  check  digestion  and 
to  retard  absorption. 

The  beverage  is  prepared  by  pouring  boiling  water  over 
freshly  ground  coffee  and  allowing  it  to  steep  for  a  few  minutes; 
or  by  permitting  boiling  water  to  percolate  through  the  ground 
coffee  in  a  special  coffee-pot.  The  coffee  should  not  be  boiled, 
as  boiling  drives  off  the  flavoring  volatile  oil  and  makes  a  heavier 
decoction  of  the  extractive  matter. 

Tea. — This  is  made  from  the  young  leaves,  which  are  prepared 
by  a  process  of  rolling,  fermenting,  and  drying.  The  constitu- 
ents are  1  to  4  per  cent,  of  caffeine,  a  minute  amount  of  theo- 
phylline, 0.6  per  cent,  of  volatile  oil,  which  imparts  the  flavor  and 
odor,  and  a  large  amount  of  tannic  acid  of  the  kind  that  precipi- 
tates gelatin,  albumin,  and  alkaloids,  and  is  strongly  astringent. 
India  and  Ceylon  teas  contain  much  more  tannic  acid  than  China 
teas  (Luke).  Green  tea  is  made  from  the  younger  leaves.  It 
contains  more  tannic  acid,  more  volatile  oil,  and  less  caffeine  than 
black  tea,  so  is  less  stimulating  and  more  astringent.  In  a 
number  of  samples  Bannister  found  that  the  black  teas  averaged 
3.24  per  cent,  of  caffeine  and  16.4  per  cent,  of  tannic  acid,  while 
the  green  teas  averaged  2.33  per  cent,  of  caffeine  and  27.14  per 
cent,  of  tannic  acid.  These  figures  do  not  correspond  with  those 
of  Spencer,  who  found  4.8  to  15.8  per  cent,  of  tannic  acid  in 
various  teas. 

It  is  claimed  that  in  the  preparation  of  the  tea  leaves  for  the 
market  about  half  the  tannic  acid  is  lost. 

The  beverage  should  be  made  by  pouring  boiling  water  upon 
the  leaves  and  allowing  them  to  steep  from  two  to  five  minutes. 
The  tea  should  not  be  boiled,  as  this  hastens  the  solution  of  the 
tannic  acid  and  drives  off  the  flavoring  oil.  As  the  tannic  acid 
and  coloring-matter  dissolve  but  slowly  in  water  that  is  not 
boiling,  a  fair  percentage  of  these  may  be  left  behind  if  the  tea 
is  soon  poured  off  the  leaves.  If  it  is  allowed  to  steep  too  long, 
the  beverage  becomes  more  deeply  colored  and  richer  in  tannic 
acid.  The  tea  which  stands  all  day  long  in  the  tea-pot  and  is 
drunk  cold  by  the  inveterate  tea-drinker  is  essentially  a  solution 
of  tannic  acid  which  would  effectively  tan  hides  into  leather. 


THEOBROMINE  AND  CAFFEINE  BEVERAGES        251 

The  amount  of  tea  used  in  making  a  cup  represents  i  or  2 
grains  (0.06-0.12  gm.)  of  caffeine,  and  the  coffee  per  cup  1  \ 
to  3  grains  (0.1-0.2  gm.),  but  always  some  of  the  caffeine  is 
left  behind.  Tea-leaves  contain  more  of  the  caffeine  than  coffee, 
but  much  less  tea  is  used  per  cup. 

Pharmacologic  Action. — Besides  the  caffeine  action,  coffee 
derives  some  of  its  properties  from  the  empyreumatic  oil,  caffeol. 
This  is  somewhat  stimulating  to  the  cerebrum,  but  in  the  alimen- 
tary tract  is  a  local  irritant.  Pincussohn  has  found  that  coffee 
results  in  a  prompt  increase  in  the  amount  and  the  acidity  of  the 
gastric  juice;  and  it  is  a  well-known  fact  that  on  the  intestines 
the  beverage  acts  as  a  laxative,  promoting  peristalsis.  These 
factors  may  not  be  of  importance  in  normal  persons,  but  they 
become  so  in  hyperesthetic  states  of  the  stomach  (hyperchlor- 
hydria,  hypersecretion,  and  gastrosuccorrhea)  and  in  diarrhea, 
so  that  coffee  may  be  contraindicated. 

Tea  seems  to  have  a  more  immediate  stimulating  effect, 
either  because  of  its  volatile  oil  or  because  absorption  is  more 
rapid.  In  "strong"  tea  the  local  action  in  the  alimentary  tract 
is  due  chiefly  to  its  tannic  acid.  This  tends  to  lessen  gastric 
secretion,  to  retard  absorption,  and  to  induce  constipation,  so 
that  tea  which  is  strong  in  tannic  acid  may  decidedly  interfere 
with  digestion.  But  because  it  contains  less  extractive  matter 
than  coffee,  properly  made  tea,  i.  e.,  tea  without  much  tannic 
acid,  is  less  disturbing  to  the  stomach  than  coffee.  In  nervous 
dyspepsia  both  tea  and  coffee  are  harmful  because  of  the  caffeine 
effect  on  the  nervous  system. 

Coffee  and  tea  are  not  nutritive  in  themselves,  and  require 
no  digestive  process  for  their  absorption.  But  the  addition  of 
milk  or  cream  and  sugar  changes  them  into  food.  In  tea  the 
tannic  acid  precipitates  the  coagulable  protein  of  the  milk,  but 
this  precipitate  digests  in  the  gastric  juice.  In  some  instances 
the  milk  and  cream  have  a  desirable  effect  by  lessening  the  local 
irritant  action  in  the  stomach,  and  by  retarding  the  absorption 
of  the  caffeine. 

As  therapeutic  amounts  of  caffeine  are  directly  antidotal  to 
the  cerebral  effects  of  alcohol,  the  after-dinner  demi-tasse  may 
have  a  special  use  when  wine  has  been  drunk  at  the  dinner.  As 
a  hot  drink  which  contains  a  volatile  oil  it  may  also  be  slightly 
stimulating  to  the  stomach.  However,  its  reputation  as  an  aid 
to  digestion  depends  more  on  habit  than  upon  any  intrinsic  power 
in  the  stomach. 

The  coffee  and  tea  habits  are  common  among  brain-workers 
(students,  writers,  etc.)  and  those  who  must  remain  awake  at 
night   (nurses,   journalists,   etc.).     The  tea  habit  is  especially 


252  PHARMACOLOGY  AND   THERAPEUTICS 

common  among  women,  whether  brain-workers  or  not,  the  "cup 
that  cheers  but  not  inebriates"  being  the  favorite  resort  of  the 
sex  to  brighten  the  gossip  of  an  afternoon  call  or  to  remove  the 
feelings  of  tiredness.  In  the  southern  United  States  the  "kola 
habit"  is  prevalent,  a  proprietary  drink  being  in  great  favor. 
Much  coffee  or  tea  may  result  in  nervousness  and  insomnia,  with 
cardiac  and  digestive  neuroses ;  but  in  such  a  case  stoppage  of  the 
beverage  will  usually  be  sufficient  to  restore  the  patient  to  normal 
in  a  short  time.  In  insomnia  caffeine  drinks  must  not  be  taken 
late  in  the  day. 

Tolerance. — The  variations  in  individual  susceptibility  to 
tea  and  coffee  are  marked,  one  person  being  wakeful  and  restless 
and  mentally  stimulated  by  a  single  cup  of  coffee  or  tea,  while 
another  will  be  unaffected  by  several  cups.  In  many  instances 
a  limited  toleration  is  set  up,  so  that  the  amount  of  tea  or  coffee 
may  be  steadily  increased  for  a  time;  but  it  is  an  interesting  fact 
that  long-continued  excessive  drinking  of  tea  or  coffee  sometimes 
results  in  a  condition  of  increased  susceptibility  which  may  per- 
sist for  months  or  even  years.  So  that  one  who  formerly  regu- 
larly drank  several  cups  of  coffee  a  day  with  apparent  impunity 
finds  himself  unable  to  drink  more  than  one  or  two  cups  without 
feeling  the  bad  effects.  The  habitual  cup  of  coffee  or  tea  seems 
to  have  little  if  any  diuretic  effect. 

The  drinking  of  tea  and  coffee  is  so  common,  and  their  harm- 
ful effects  are  so  evident,  that  physicians  are  prone  to  proscribe 
these  beverages  rather  than  to  prescribe  them. 

Before  leaving  this  subject  I  should  like  to  say  to  every  stu- 
dent that  if  he  gets  into  a  state  in  which  night  after  night  he 
cannot  work  without  coffee,  he  is  drawing  upon  his  reserves,  so 
that  when  he  needs  to  make  a  spurt  he  will  be  unable  to  do  so. 
In  such  a  case  what  he  really  needs  to  clear  his  brain  is  a  short 
period  of  rest  from  excessive  study,  with  open-air  exercise  and 
good  sleep.  If  he  is  to  have  some  special  test  of  his  knowledge, 
such  as  an  examination,  then  coffee  may  enable  him  to  do  his 
best  intellectual  work,  but  an  excessive  amount  will  only  make 
him  nervous  and  unable  to  think  clearly. 

CHOCOLATE 

Chocolate  is  the  paste  made  from  the  ripe  seeds  of  the  choco- 
late plant,  Theobroma  cacao,  after  they  have  been  sweated, 
dried,  roasted,  and  deprived  of  their  shells  (the  so-called  "cocoa 
nibs").  The  sweating  or  fermentation  process  removes  practi- 
cally all  the  tannic  acid  and  some  of  a  bitter  substance  which  is 
present  in  the  ripe  seed,  and  the  roasting  brings  out  the  chocolate 
flavor.     Chocolate  contains  from  0.3  to  2  per  cent,  of  theobro- 


NUX  VOMICA 


253 


mine  (according  to  some  authorities,  also  caffeine  up  to  0.35  per 
cent.),  10  per  cent,  of  starch,  15  per  cent,  of  vegetable  protein, 
and  30  to  50  per  cent,  of  a  peculiar  fat  which  is  known  as  cocoa- 
(cacao)  butter.  (See  Fats,  Part  I.)  Pure  chocolate  is  not 
pleasant  to  the  taste,  so  for  eating  and  drinking  it  is  regularly 
sweetened  with  sugar  and  often  flavored  with  vanilla.  It  is 
highly  nutritive,  and  has  been  shown  by  Weissmann,  Zuntz,  and 
others  to  be  almost  completely  digestible,  but  the  fat  acts  in  the 
stomach  to  retard  both  the  secretion  of  gastric  juice  and  the  motor 
functions,  i.  e.,  the  emptying  of  the  stomach,  so  chocolate  cannot 
be  taken  in  large  quantities.  Neumann  replaced  a  fixed  allow- 
ance of  bread,  sausage,  pork,  sugar,  and  cheese  with  an  amount 
of  cocoa  and  cocoa-butter  of  equal  caloric  value.  The  diet  was 
moderately  satisfactory,  but  he  developed  a  severe  headache 
which  he  attributed  to  the  theobromine. 

Cocoa  is  a  powdery  preparation,  made  from  chocolate  by 
removing  a  portion  of„  the  cocoa-butter  by  hydraulic  pressure, 
with  or  without  heat.  The  dried  residue  is  ground  to  a  very 
fine  powder,  so  that  it  may  be  more  readily  mixed  with  water. 
The  proportion  of  theobromine  in  cocoa  is  thus  somewhat  higher 
than  in  chocolate,  while  the  fat  is  less,  constituting  only  15  to  30 
per  cent.  Inferior  cocoas  are  made  by  diluting  the  chocolate 
with  starch,  thus  reducing  the  theobromine  as  well  as  the  fat. 
The  so-called  Dutch  process  is  one  of  partial  saponification  of  the 
fat  with  an  alkali,  to  make  it  miscible  with  water. 

The  beverage  "cocoa"  is  made  by  boiling  the  cocoa  powder 
with  water  or  milk  for  at  least  five  minutes,  so  that  its  starch 
may  be  properly  hydrolyzed;  otherwise  it  is  nothing  but  a  crude 
mixture  from  which  the  powder  tends  to  separate.  When  it  is 
made  with  milk  and  is  sweetened  with  sugar,  it  has  a  high  food 
value;  a  cupful  of  such  a  beverage,  prepared  with  about  10  grams 
of  cocoa,  giving  a  nutritive  value  of  peihaps  250  calories.  Such 
a  drink  may  sometimes  be  taken  by  invalids  for  its  food  value. 

Chocolate  is  sometimes  made  into  a  beverage,  but  it  contains 
so  much  fat  and  requires  so  much  sugar  that  it  is  rich  and  sweet 
and  is  heavy  in  the  stomach.     It  is  not  suited  for  invalids. 

Cocoa  and  chocolate  have  the  properties  of  theobromine, 
but  kidney  tolerance  is  soon  established,  so  that  no  "diuresis" 
results  from  the  habitual  cup. 

NUX  VOMICA 
Nux  vomica  is  the  dried  ripe  seed  of  Strychnos  Niix-vomica 
(Fam.  Loganiacea) ,  yielding,  when  assayed,  not  less  than  1.25 
per  cent,  of  strychnine.     It  is  native  in  India,  Cochin-China, 
and  Australia. 


254  PHARMACOLOGY   AND   THERAPEUTICS 

Constituents. — The  alkaloids,  strychnine  and  brucine,  the 
two  being  present  in  more  or  less  equal  quantities.  They  exist 
in  combination  with  igasuric  acid,  an  acid  which  makes  a  dark 
greenish  color  with  ferric  salts. 

Preparations  and  Doses. — /.  Of  Nux  Vomica. — All  are  as- 
sayed. 

Nux  vomica  1.25  per  cent,  of  strychnine.    1  grain  (0.06  gm.). 

Extract 5  per  cent y4  grain  (0.015  gm.). 

Fluidextract 1  per  cent 1  minim  (0.06  c.c). 

Tincture 0.1  per  cent 10  minims  (0.6  c.c). 

Ten  minims  of  the  tincture  of  nux  vomica  must  assay  to  con- 
tain not  less  than  y-g-g-  grain  (0.0006  gm.)  of  strychnine,  equiva- 
lent to  about  gV  grain  (0.0008  gm.)  of  strychnine  sulphate. 

77.  Of  Strychnine.- — The  official  salts  are  the  nitrate,  soluble 
in  42  parts  of  water  and  in  120  of  alcohol,  and  the  sulphate, 
soluble  in  31  parts  of  water  and  in  65  of  alcohol.  Dose,  -^ 
grain  (0.001  gm.).  The  maximum  beginning  dose  is  -^  grain 
(0.003  gm.).  According  to  their  molecular  weights,  the  nitrate 
contains  84  per  cent,  of  pure  strychnine,  and  the  sulphate  77  per 
cent.  In  dry  air  the  sulphate  tends  to  become  stronger  by  the 
loss  of  its  water  of  crystallization,  while  the  nitrate  is  permanent. 
The  other  preparations  of  strychnine  are: 

Citrate  of  iron  and  strychnine,   1  per  cent.     Dose,   2  grains 

(0.13  gm.). 
Elixir  of  the  phosphates  of  iron,  quinine,  and  strychnine.     Dose, 
1    dram  (4  c.c.)   =  ■£%  grain  (0.001  gm.)  strychnine  and  yg- 
grain  quinine. 
Syrup  of  the  phosphates  of  iron,  quinine,  and  strychnine.     Dose, 
1  dram  (4  c.c.)  =  ■$-$  grain  (0.0008  gm.)  strychnine  and  if 
grains  quinine. 
Glycerite  of  the  phosphates  of  iron,  quinine,  and  strychnine. 
This  is  four  times  the  strength  of  the  syrup,  for  the  prepara- 
•  tion  of  which  it  is  kept  as  a  stock  solution. 
Compound   syrup   of  the  hypo  phosphites,  2   drams  (8  c.c.)  = 

strychnine,  TV  grain  (0.001  gm.),  and  quinine,  y%  grain. 
Compound  laxative  pills — aloin,  3-  grain,  extract   belladonna, 
-g-  grain,  ipecac,  yg-  grain,    strychnine,    the   pure    alkaloid, 
T^o  grain  (0.0005  gm.). 
Pharmacologic  Action. — On  man  brucine  has  the  same  type 
of  action  as  strychnine,  but  it  has  been  estimated  to  be  only 
3^  to  -§-  as  strong,  hence  the  strychnine  practically  represents 
the  nux  vomica  action. 

Alimentary  Tract. — The  taste  is  intensely  bitter — so  bitter, 
indeed,  that  it  is  perceptible  in  a  solution  of  1  part  in  1,000,000 


NUX  VOMICA  255 

of  water.  As  the  result  of  the  bitterness  there  is  a  reflex  flow  of 
saliva,  and  the  drug  has  the  effeet  of  a  bitter  upon  the  taste- 
buds.     (See  Bitters.) 

After  absorption  into  the  blood,  the  strychnine  effect  upon 
the  spinal  cord  results  in  an  increase  in  the  tone  of  the  muscles 
of  the  stomach  and  intestines,  and  probably  in  an  increase  of 
reflex  secretory  activity. 

Absorption  is  rapid,  especially  from  the  intestines.  As 
reported  by  one  investigator,  convulsions  came  on  in  thirty 
minutes  after  the  injection  of  1^  grains  into  the  stomach  of  a 
cat,  while  convulsions  followed  injection  of  the  same  amount  into 
the  small  intestine  in  ten  minutes,  and  a  similar  injection  into 
the  rectum  in  seven  minutes.  Ryan  (191 2)  found  absorption  of 
an  aqueous  solution  quite  rapid  from  the  stomach.  He  used  the 
small  pouch  of  the  Pawlow  stomach,  so  as  to  prevent  passage  of 
the  strychnine  into  the  intestines,  while  allowing  the  normal 
motor  activity  to  go  on. 

Cerebrum. — There  is  a  slight  stimulation  of  the  intellect  and 
of  the  motor  areas,  in  kind  like  that  of  caffeine.  But  in  degree 
it  is  much  less  marked,  so  that  strychnine  is  not  a  pronounced 
intellectual  stimulant,  and  has  much  less  effect  than  caffeine  in 
opposing  sleep.  The  perceptions  are  all  stimulated,  pain  being 
more  keenly  felt,  the  senses  of  smell  and  taste  more  discriminat- 
ing, that  of  hearing  more  acute,  that  of  touch  more  sensitive. 
These  are  all  central  effects.  The  sight  is  also  rendered  more 
keen,  particularly  in  distinguishing  colors;  and  as  this  effect  is 
produced  in  only  one  eye,  if  the  drug  is  dropped  into  that  eye  or 
if  it  is  injected  into  the  immediate  vicinity  of  that  eye,  the 
strychnine  is  believed  to  act  peripherally  on  the  retinal  elements, 
which  it  reaches  through  the  lymph-spaces.  The  optic  centers 
are  also  probably  stimulated.  Through  these  two  factors,  large 
doses  of  strychnine  injected  into  the  temple,  in  partial  optic 
nerve  atrophy,  will  sometimes  bring  about  an  improvement  in 
the  sight. 

Spinal  Cord. — If  a  poisonous  dose  of  strychnine  is  admin- 
istered to  an  animal,  a  very  slight  stimulus,  such  as  the  prick  of 
a  pin,  a  touch,  or  the  jarring  of  the  table  upon  which  the  animal 
lies,  will  send  it  into  convulsions.  Something  has  happened  to 
make  a  tremendous  muscular  response  to  an  ordinary  stimulus. 
What  does  the  strychnine  do?     Note  the  following  experiments: 

1.  Expose  the  sciatic  nerve  of  a  frog  and  ligate  the  rest  of  the 
limb  so  as  to  leave  the  nerve  outside  of  the  ligature.  This 
leaves  the  nervous  connections  between  the  spinal  cord  and  the 
lower  part  of  the  limb  intact,  but  cuts  off  the  limb's  circulatory 
connection  with  the  rest  of  the  body.     Inject  strychnine  into  the 


256  PHARMACOLOGY  AND   THERAPEUTICS 

leg  below  the  ligature,  where  it  can  act  locally  on  nerve-endings 
and  nerve-trunk.  The  reflexes  are  still  intact,  because  the  nerve 
is  left  outside  of  the  ligature,  but  the  strychnine  does  not  get  to 
the  spinal  cord  because  the  circulation  is  cut  off.  The  prick  of  a 
pin  below  the  ligature  now  meets  with  just  the  usual  response; 
therefore  the  strychnine  does  not  stimulate  the  nerve-endings 
or  nerves,  either  sensory  or  motor.  If,  now,  strychnine  is  in- 
jected above  the  ligature,  the  prick  of  a  pin  below  the  ligature 
results  in  convulsions. 

2.  Poidsson's  Experiment. — Dip  a  frog  in  5  per  cent,  cocaine 
solution  until  its  skin  is  just  anesthetized,  so  as  to  cut  off  any 
afferent  impulses  from  the  surface;  then  give  a  large  dose  of 
strychnine,  and  no  convulsions  result.  Now  generate  afferent 
impulses  by  stimulating  the  nerve-trunks,  and  convulsions 
follow. 

3.  Claude  Bernard's  Experiment. — Cut  the  posterior  nerve- 
roots  to  prevent  afferent  impulses  from  getting  to  the  cord, 
strychnize  the  frog,  and  no  convulsions  result.  Stimulate  the 
central  cut  end  and  convulsions  follow,  whether  the  roots  have 
been  cut  peripheral  or  central  to  the  ganglia. 

These  experiments  show — (1)  That  the  drug  does  not  act 
upon  the  peripheral  nerves  or  the  posterior  root  ganglia.  (2) 
That  it  does  not  of  itself  produce  motor  effects.  (3)  That  it 
causes  increased  motor  response  to  afferent  impulses,  i.  e.,  to 
external  stimuli. 

The  convulsions  are,  therefore,  reflex  in  nature,  the  strych- 
nine acting  on  structures  in  the  cord  itself  and  resulting  in  greatly 
increased  reflex  excitability. 

What  is  a  reflex?  If  the  eye  is  exposed  to  a  light,  the  pupil 
contracts;  if  some  irritating  dust  gets  into  the  nose,  it  causes 
sneezing.  These  are  motor  reflexes.  If  about  dinner  time  the 
appetizing  odor  of  food  is  recognized,  the  stomach  begins  to 
secrete  gastric  juice;  if  a  substance  of  bitter  taste  gets  into  the 
mouth,  the  saliva  flows.  These  are  secretory  reflexes.  In  each 
case  there  is  some  peripheral  stimulus,  these  actions  not  occur- 
ring otherwise,  and  the  response  is  involuntary.  A  reflex,  then, 
is  an  involuntary  secretory  or  motor  response  to  an  afferent 
impulse. 

Reflex  actions  are  usually  purposeful  and  definite,  the  same 
kind  of  response  regularly  following  stimulation  at  a  given  place. 
A  piece  of  dust  on  the  conjunctiva  ordinarily  results  in  instant 
closure  of  the  eye;  a  teaspoonful  of  mustard  placed  in  the  stomach 
regularly  results  in  vomiting;  the  dipping  of  a  frog's  hind  leg  in 
acetic  acid  regularly  results  in  a  drawing  of  the  leg  away  from  the 
offending  substance  and  an  attempt  to  wipe  it  away  with  the 


NUX   VOMICA 


257 


other  leg.  The  afferent  impulses,  therefore,  do  not  travel  at 
random  to  any  motor  cells,  but  would  seem  to  travel  to  those 
motor  cells  which  can  produce  the  proper  purposeful  motor 
response.  That  is,  for  each  afferent  impulse  there  seems  to  be 
in  the  cord  one  particular  path  or  group  of  paths  along  which  it 
travels  to  reach  the  motor  or  secretory  cells,  this  one  path  ordi- 
narily being  open  to  it,  while  all  other  paths  are  closed  to  it.  By 
training,  certain  new  paths  are  opened  up,  or,  in  other  words, 
actions  which  are  at  first  voluntary  become  reflex,  as  in  piano- 
playing,  skating,  and  most  of  our  activities.  At  first  the  will  is 
necessary  to  insure  the  desired  response  to  the  stimulus,  as  that 
the  linger  shall  strike  a  certain  key  of  the  piano  when  the  eye  sees 
a  certain  printed  note.  But  by  constant  repetition  a  path  is 
established  so  that  the  player  comes  to  strike  the  proper  key 
involuntarily  as  soon  as  the  eye  perceives  the  note. 

Reflexes  are  of  three  kinds,  viz. : 

(1)  The  simple  reflexes,  which  involve  only  one  muscle,  as 
in  winking  the  eye.  (2)  The  coordinated  reflexes,  in  which, 
during  the  contraction  of  one  set  of  muscles,  there  is  inhibition 
of  the  opposing  muscles;  these  are  the  ordinary  purposeful 
reflexes  of  our  bodies.  (3)  The  convulsive  reflexes,  which  are 
incoordinated  because  all  the  muscles  are  stimulated,  and  there 
is  no  inhibition.  Since  all  the  muscles  contract,  the  stronger 
predominate.  Convulsive  reflexes  are  exaggerated,  purposeless, 
and  harmful,  and  are  due  to  some  derangement  of  coordina- 
tion. 

How  does  strychnine  produce  convulsive  reflexes?  Baglioni 
(1900)  performed  an  experiment  which  has  become  classic.  He 
exposed  the  spinal  cord  of  a  decapitated  frog  at  the  brachial 
plexus,  and  removed  the  pia  with  its  vessels  to  cut  off  circulatory 
connection  with  the  parts  of  the  cord  above  and  below.  He  then 
painted  the  denuded  area  with  a  solution  of  strychnine,  and  thus 
poisoned  the  part  of  the  cord  through  which  afferent  impulses 
from  the  fore-limb  would  have  to  pass,  but  did  not  poison  the 
rest  of  the  cord. 

1.  On  stimulating  the  hind-limb,  he  got  the  usual  normal  re- 
flex response,  the  poisoned  area  being  beyond  the  influence  of  such 
a  stimulus.  When  he  pinched  the  foot,  the  leg  was  drawn  up;  if 
he  placed  a  drop  of  acetic  acid  upon  the  leg,  the  other  leg  would 
be  drawn  up  to  wipe  it  off.  This  proved  that  the  sensory  nerves, 
the  synapses,  and  the  motor  cells  in  the  lower  part  of  the  cord 
were  unpoisoned  and  acting  normally! 

2.  But  when  he  pinched  or  pricked  one  of  the  fore-limbs  or 
dipped  it  in  acid,  there  resulted  a  convulsion  of  the  whole  body, 
both  hind-limbs  and  fore-limbs  being  involved.     In  other  words, 

17 


258 


PHARMACOLOGY  AND  THERAPEUTICS 


when  the  afferent  impulse  passed  through  an  unstrychnized 
portion  of  the  cord,  the  response  was  the  usual  one;  but  when 
the  impulse  passed  through  a  strychnized  area,  there  was  an 
abnormal  response,  not  only  in  the  muscles  usually  affected  by 
such  an  impulse  in  an  unpoisoned  animal,  but  also  in  a  large 
number  of  the  other  muscles  of  the  body.  These  muscles  went 
into  a  convulsive  state,  whether  their  motor  cells  were  in  the 
poisoned  area  or  not.     Therefore  the  action  of  the  strychnine  is 


Fig.  34. — Kolliker's  schema  to  show  the  reflex  arc.  A  shows  the  posterior 
root-fiber  (black)  dividing  and  spreading  up  and  down  the  cord,  and  connecting 
with  many  motor  cells  (red)  through  its  synapses  (black  ramifications).  B  shows 
the  posterior  root-fiber  connecting  through  the  first  synapse  of  the  afferent  sys- 
tem with  an  intermediate  neuron  (green),  which  in  turn  connects  with  numerous 
motor  cells  (red)  through  its  synapses  (after  Howell). 


neither  on  the  motor  cells  themselves  nor  on  the  synapses  about 
the  motor  cells;  and  is  in  all  probability  on  either  the  intermediary 
neurons  in  the  cord  or  the  first  synapses  of  the  afferent  system. 

If  the  dose  given  is  just  a  little  less  than  enough  to  produce 
convulsive  twitching,  the  response  of  the  usual  muscles  is  greater 
than  normal,  but  in  the  usual  purposeful  way;  and  this  is  be- 
lieved to  be  due  to  the  greater  transmission  of  the  afferent  im- 
pulses. There  is  no  satisfactory  evidence  that  the  motor  cells 
themselves  are  stimulated. 


NUX   VOMICA 


259 


Hence  the  action  of  strychnine  upon  the  spinal  cord  may  be 
thought  of  as  not  only  to  facilitate  the  passage  of  afferent  im- 
pulses to  their  usual  motor  cells,  but  to  open  up  the  paths  to  the 
other  motor  cells,  so  that  the  impulses  may  reach  and  affect  cells 
ordinarily  beyond  their  influence.  In  other  words,  strychnine 
increases  reflex  activity  by  facilitating  the  passage  of  afferent  im- 
pulses in  the  cord  (across  and  up  and  down  the  cord).  It  may 
directly  stimulate  the  motor  cells  themselves,  but  this  is  not 
proved. 

Sherrington's  Theory. — As  has  been  pointed  out,  a  certain 
stimulus  leads,  normally,  through  coordination,  not  only  to  con- 
traction of  a  certain  group  of  muscles,  but  also  to  relaxation  of 
the  opposing  group;  and  the  same  stimulus,  after  a  toxic  dose  of 
strychnine,  induces  contraction  not  only  in  the  usual  group,  but 
also  in  the  antagonists.  Therefore,  under  strong  strychnine 
stimulation  all  the  muscles  contract,  so  that,  of  two  sets  of 
opposing  muscles,  the  stronger  regularly  predominate.  For 
example,  if  an  animal  poisoned  with  strychnine  attempts  to 
open  its  mouth,  both  the  opening  and  closing  muscles  are  ex- 
cited, and  as  the  closing  muscles  are  the  stronger,  the  mouth 
becomes  all  the  more  tightly  closed.  If  a  man  under  an  excess- 
ive dose  of  strychnine  tries  to  walk,  his  gait  is  spastic,  and  his 
legs  are  more  or  less  stiff,  because  all  the  muscles  are  in  an  ex- 
citable contractile  state.  Sherrington's  belief  is  that  the  strych- 
nine overaction  is  due  to  a  change  of  the  usual  relaxation  or 
inhibition  of  the  opposing  muscles  into  contraction  or  excitation, 
and  the  will  is  in  complete  abeyance.  This  well  explains  the 
exaggerated  and  convulsive  reflexes,  and  the  spasticity,  but  not 
the  wide-spread  response  to  a  stimulus. 

Following  up  this  theory,  Bayliss  has  been  able  to  show  that, 
after  poisonous  amounts  of  strychnine,  stimulation  of  the  de- 
pressor nerve  will  result  in  a  rise  in  arterial  pressure,  i.  e.,  the 
depressor  nerve  is  no  longer  an  inhibitory  nerve,  but  an  excita- 
tory nerve. 

Tone. — Tone  is  a  condition  of  readiness  to  respond  to  stimu- 
lus. All  the  muscles,  both  voluntary  and  involuntary,  are  in  a 
constant  state  of  tone,  i.  e.,  they  are  in  a  condition  of  slight  con- 
traction, so  that  they  are  drawn  up  in  readiness  to  work  the 
moment  a  stimulus  comes.  One  or  two  experiments  to  determine 
the  nature  of  muscular  tone  are  of  interest : 

1.  If  a  frog  is  decapitated  and  the  sciatic  nerve  of  one  side 
cut,  the  leg  on  the  cut  side  is  more  relaxed  than  the  other  leg, 
i.  e.,  severance  of  the  leg  from  its  connection  with  the  central 
nervous  system  results  in  greater  relaxation  than  normal,  or  loss 


260  PHARMACOLOGY  AND   THERAPEUTICS 

of  its  tone.  It  is  evident  then  that  the  tone  of  the  leg  is  due  to 
the  reception  of  stimuli  from  the  motor  cells  of  the  spinal  cord. 

2.  If  a  frog's  skin  is  anesthetized  by  immersing  the  frog  in 
5  per  cent,  cocaine  to  cut  off  external  stimuli,  or  its  posterior 
nerve-roots  cut  to  prevent  any  afferent  impulses  from  reaching 
the  cord,  there  results  marked  muscular  relaxation,  i.  e.,  loss  of 
tone  on  both  sides.  Evidently,  therefore,  tone  of  voluntary 
muscle  is,  at  least  in  great  part,  dependent  upon  the  reception  in 
the  cord  of  afferent  impulses.  Tone  is,  therefore,  largely  a 
manifestation  of  reflex  activity.  Strychnine  heightens  tone  by 
increasing  reflex  excitability,  and  on  this  property  most  of  the 
therapeutic  usefulness  of  strychnine  depends.  It  is  the  best  of 
our  genuine  "tonics." 

Resume. — The  therapeutic  use  of  strychnine  is  to  open  up  the 
normal  paths  in  the  cord  when  they  become  clogged,  so  that  an 
afferent  impulse  can  reach  the  usual  motor  cells  with  greater 
facility.  In  other  words,  it  is  to  increase  tone  and  the  usual 
purposeful  reflexes.  Therapeutically,  there  is  no  desire  to  have 
an  impulse  affect  other  cells  than  the  usual  ones.  The  poisonous 
action  is — (i)  To  open  widely  the  regular  paths  to  motor  cells 
(overtone) ;  (2)  to  interfere  with  coordination  by  changing  the 
normal  inhibition  of  opposing  muscles  into  excitation  (spasticity) ; 
and  (3)  to  open  up  great  numbers  of  new  paths,  so  that  an  impulse 
can  reach  and  excite  large  numbers  of  motor  cells  that  are  ordi- 
narily beyond  its  influence  (general  spinal  convulsions). 

Peripheral  Nerves. — There  is  no  effect  in  man.  In  the  frog 
large  quantities  may  depress  the  ends  of  the  vagus  nerves  and  of 
the  sensory  and  motor  nerves;  and  in  animals  in  which  strychnine 
convulsions  have  been  prevented  by  spinal  analgesia,  a  curare- 
like effect  on  motor  nerve-endings  has  been  suspected. 

Comparison  of  Strychnine  and  Caffeine. — In  their  action  upon 
the  central  nervous  system  caffeine  and  strychnine  are  stimu- 
lants of  the  same  class.  But  caffeine  affects  the  cerebrum  most, 
while  strychnine  acts  most  upon  the  spinal  cord.  Both  stimu- 
late the  medullary  centers  more  or  less  equally. 

Muscle. — No  direct  action,  though  improved  muscular  power 
results  from  increased  tone  and  heightened  reflex  activity. 

Circulation. — In  perfusion  of  the  isolated  heart,  only  high 
concentrations  of  strychnine  have  any  effect,  so  the  heart  muscle 
is  not  stimulated  by  any  dose  that  would  be  given  to  man.  In 
perfusing  an  isolated  viscus  or  limb  there  is  no  effect  upon  the 
arteries.  In  the  intact  mammal,  after  therapeutic  doses,  there 
may  be  a  slight  slowing  of  the  pulse  from  a  moderate  stimulation 
of  the  vagus  center,  and  a  slight  rise  of  arterial  pressure  from 
stimulation  of  the  vasoconstrictor  center,  but,  as  a  rule,  the 


Fig.  35._Strychnine  sulphate,  0.2  mg.  per  kilo,  no  effect  on  circulatory  organs 
Upper  tracing,  auricle;  middle,  ventricle;  lower,  blood-pressure;  upper  line  of 
figures,  pulse-rate.     (Tracing  made  by  Dr.  C.  C.  Lieb.) 


NUX  VOMICA  261 

effect  on  blood-pressure  is  very  slight,  if  any.  In  cases  of  general 
weakness  the  improvement  in  general  muscular  tone  may  have 
a  good  effect  upon  the  circulation,  but  it  is  a  mistaken  idea 
among  physicians  that  strychnine  is  a  direct  stimulant  to  the 
heart. 

To  test  strychnine  clinically.  Cook  and  Briggs  injected  -^ 
to  yu  grain  (0.001-0.006  gm.).  In  persons  ill  enough  to  be  in 
bed,  they  obtained  a  slow  rise  of  pressure  lasting  from  one  to 
four  hours.  There  was  no  effect  on  the  pressure  in  normal  per- 
sons or  in  patients  that  were  moribund.  Richard  C.  Cabot 
(1904)  made  about  5000  observations  of  the  arterial  pressure 
before  and  after  strychnine  in  50  fever  cases,  including  31  of 
typhoid  and  4  of  pneumonia.  In  32  of  the  50  cases  the  drug 
was  given  by  mouth,  in  18  hypodermatically.  The  usual  daily 
dosage  totaled  £  grain  (0.08  gm.).  In  16  cases  there  was  a 
rise  in  blood-pressure  of  5  mm.  or  more;  in  24  cases  no  change 
in  blood-pressure,  and  in  17  cases  a  fall  of  pressure;  the  average 
change  in  blood-pressure  was  no  greater  than  in  that  of  the 
controls  (18  cases).  These  experiments  must  not  be  too  con- 
vincing, however,  for  we  have  evidence  in  man  that  the 
circulation  may  be  greatly  improved  without  the  arterial  pressure 
being  raised.  (See  Digitalis.)  Yet  they  are  in  line  with  the 
findings  of  the  experimental  laboratory. 

During  a  convulsion  the  blood-pressure  is  very  high,  because 
of  the  great  general  muscular  contraction,  but  this  is  of  no  in- 
terest to  us  in  therapeutics.  The  skin  vessels,  especially  those  of 
the  face,  may  be  dilated  from  a  special  vasodilator  action. 

Respiratory. — Large  therapeutic  doses  cause  a  deepening 
and  quickening  of  respiration  from  stimulation  of  the  respiratory 
center.  Large  poisonous  doses  overwhelm  and  quickly  exhaust 
the  center.  Death  takes  place  from  asphyxia,  due  either  to  the 
setting  of  the  respiratory  muscles  during  a  convulsion,  or  to 
exhaustion  of  the  respiratory  center  (between  the  convulsions). 

Under  therapeutic  doses,  the  bronchial  muscles  are  improved 
in  tone,  so  the  drug  may  be  useful  in  relaxed  conditions  of  the 
bronchi;  while  in  spasmodic  conditions,  as  in  bronchial  asthma, 
it  will  be  harmful. 

In  cough  the  reflex  excitability  is  increased,  so  that  when 
there  is  abundant  secretion  to  be  coughed  up,  strychnine  may 
change  a  weak,  ineffective  cough  into  an  effective  one.  But 
when  the  cough  is  from  a  dry  or  tickling  throat  and  cannot  be 
made  effective  in  getting  rid  of  the  offending  stimulus,  strych- 
nine only  uselessly  increases  the  cough  and  distresses  the  patient. 

Metabolism. — Because  of  the  heightened  muscular  tone  there 
is  some  increased  metabolism,  as  shown  by  increased  absorption 


262  PHARMACOLOGY  AND   THERAPEUTICS 

of  oxygen  and  increased  output  of  carbon  dioxide.  In  convul- 
sions the  metabolism  is  greatly  increased. 

Temperature. — There  is  greater  production  of  heat,  owing  to 
the  increased  metabolism,  and  greater  dissipation  of  heat  from 
the  dilatation  of  the  cutaneous  vessels;  the  net  change  is  not 
enough  to  be  important.  During  a  convulsion  there  is  a  great 
production  of  heat. 

Excretion. — Some  of  the  drug  is  oxidized  and  destroyed  quite 
rapidly  in  the  tissues;  the  remainder  is  eliminated  in  the  urine. 
It  can  be  detected  in  the  urine  very  soon  after  the  dose  is  ad- 
ministered, and  most  of  it  is  excreted  within  twelve  hours,  but 
traces  may  be  present  for  four  or  five  days.  From  maximum 
doses  cumulative  poisoning  may  occur,  though  this  is  infrequent. 
In  strychnine  poisoning  the  urine,  concentrated  by  boiling  and 
injected  into  a  frog,  may  give  the  characteristic  convulsions. 

Tolerance. — Hare  has  given  some  evidence  that  there  is  no 
tolerance  for  strychnine  (Amer.  Jour.  Physiol.,  v).  Worth  Hale 
produced  it  with  difficulty  in  dogs,  but  more  readily  in  guinea- 
pigs.  In  human  beings,  if  the  dose  is  increased  very  slowly,  a 
certain  amount  of  tolerance  may  be  set  up.  For  example,  if  a 
patient  is  started  on  ■£$  grain  three  times  a  day,  the  dose  may 
be  slowly  and  steadily  increased  until  in  five  or  six  weeks  the 
patient  is  getting  ^  or  £  grain  three  times  a  day  with  no  un- 
toward symptoms,  though  such  dosage  would  have  been  poison- 
ous in  the  beginning.  In  locomotor  ataxia,  progressive  muscular 
atrophy,  optic  nerve  atrophy,  etc.,  Troisfontaine  has  reached 
doses  of  ^  to  ^  grain  daily,  and  Graeme  Hammond  has 
been  able  to  increase  the  daily  dosage  to  f  or  f  of  a  grain, 
without  untoward  effects.  Other  neurologists  have  had  similar 
experience  in  producing  tolerance  to  these  large  doses. 

Toxicology. — After  the  repeated  administration  of  large  doses 
of  strychnine  the  patient  may  become  restless  and  nervous  and 
twitchy,  may  make  abrupt  movements,  as  shrugging  one  shoulder 
or  twitching  the  fingers  or  an  arm  or  a  leg,  and  may  feel  a  stiff- 
ness of  the  face  muscles,  especially  when  he  laughs,  or  a  stiffness 
in  the  gait.  These  are  the  first  signs  of  strychnine  poisoning, 
and  the  drug  should  at  once  be  stopped.  If  considered  neces- 
sary, spinal  sedatives,  such  as  bromides,  may  be  administered. 

In  a  more  marked  stage  of  poisoning  the  twitches  become 
spasms,  and  soon  there  are  general  convulsions  of  the  spinal 
type.  During  a  convulsion  all  the  voluntary  muscles  are  affected, 
so  of  two  opposing  sets  of  muscles  the  action  of  the  stronger 
set  predominates.  The  extensors  are  mostly  the  stronger, 
hence  the  arms,  legs,  and  back  are  extended  and  the  head  is 
thrown  back;  in  addition  the  hands  may  be  clenched  and  the 


NUX   VOMICA  263 

eyes  wide  open,  and  there  is  a  ghastly  grain,  the  risus  sardonicus, 
produced  by  the  spasmodic  drawing  out  of  the  corners  of  the 
mouth.  During  the  poisoning  the  mind  remains  clear,  conse- 
quently there  is  great  anxiety  on  the  part  of  the  patient;  and 
while  the  convulsions  last  there  is  great  muscular  pain  (cramps). 

The  convulsion  is  at  first  tonic,  that  is,  the  contraction  is 
continuous,  making  the  muscle  rigid;  it  then  changes  to  clonic, 
i.  e.,  rhythmic  intermittent  contraction;  then  it  ceases.  Before 
another  convulsion  sets  in  there  is  a  moment  of  great  muscular 
relaxation,  with  complete  prostration  and  soreness  of  the  muscles. 
If  the  poisoning  is  severe,  the  convulsions  follow  in  rapid  succes- 
sion, being  brought  on  by  the  slightest  stimulus — the  slamming 
of  a  door,  a  touch,  a  flash  of  light,  a  puff  of  air,  the  moving  of  a 
limb,  or  a  voluntary  effort.  In  mammals,  after  a  few  convulsions, 
there  is  complete  exhaustion  with  collapse.  Death  takes  place 
from  asphyxia,  due  either  to  exhaustion  of  the  respiratory  center 
or  to  continuous  spasm  of  the  respiratory  muscles.  The  heart 
may  keep  on  beating  for  some  time  after  respiration  has  ceased. 
It  is  put  under  great  strain  by  the  repeated  convulsions.  Death 
usually  takes  place  inside  of  two  hours,  and  after  convulsions  set 
in  it  is  probably  impossible  to  save  the  patient. 

One-twelfth  grain  of  strychnine  sulphate  in  a  woman  has 
given  beginning  toxic  symptoms;  f  grain  in  a  day  has  been 
well  borne  by  patients  who  had  become  tolerant  to  the  drug. 
Shoemaker  reports  recovery  in  three  hours  of  a  student  who  had 
taken  thirty  yw  grain  pills  of  the  sulphate.  A  dose  of  4  grains 
has  been  recovered  from;  in  all  probability  it  was  not  absorbed. 
A  dose  of  y-5-g-  grain  (0.0004  gm-)  Per  kilo  intravenously  or 
intramuscularly  is  invariably  fatal  to  dogs  (Githens  and  Meltzer). 

Treatment. — If  the  drug  has  been  swallowed,  but  symptoms 
of  poisoning  have  not  yet  come  on,  the  stomach  should  be 
thoroughly  lavaged,  and  tannic  acid  or  even  tea  administered  to 
form  the  rather  insoluble  strychnine  tannate,  and  thus  retard 
absorption.  The  tannate  formed  must  be  washed  out  at  once, 
as  it  is  slowly  absorbed.  If  tea  is  employed,  immediate  lavage 
is  particularly  necessary,  lest  the  caffeine  of  the  tea  be  absorbed 
and  increase  the  poisonous  effect.  If  the  convulsions  have  begun, 
lavage  may  also  be  indicated;  but  usually,  because  of  the  rapid 
absorption  of  the  drug,  it  is  useless  at  this  stage.  Before  a 
stomach-tube  can  be  inserted  it  may  be  necessary  to  administer 
ether.  In  fact,  ether  is  said  to  have  proved  an  effective  antidote 
in  dogs. 

The  systemic  treatment  consists  of — 

1.  Spinal  Cord  Sedatives. — For  quick  action,  chloroform  or 
ether  by  inhalation.     But  this  must  be  used  with  caution ;  for  both 


264  PHARMACOLOGY  AND   THERAPEUTICS 

chloroform  and  ether  tend  to  increase  the  already  serious  mus- 
cular relaxation  between  the  convulsions,  and  chloroform  de- 
presses the  respiratory  center.  For  prolonged  effect,  bromides 
in  large  dose,  \  ounce  (15  gm.)  by  mouth  or  rectum.  These 
are  directly  antagonistic  to  strychnine  in  their  action  upon  the 
cord.  Chloral  hydrate  is  sometimes  used;  but  in  safe  amounts 
it  has  too  little  action  upon  the  cord,  and,  like  chloroform,  has 
the  disadvantage  of  being  very  depressing  to  the  respiratory 
center.  Failure  of  this  center  in  strychnine  poisoning  threatens 
at  any  moment.  Paraldehyde  does  not  depress  the  respiratory 
center,  and  may  be  of  use  in  some  cases.  Morphine  should  not 
be  employed,  for  it  not  only  depresses  the  respiratory  center, 
but  also  fails  to  antagonize  the  strychnine  effect  upon  the  cord. 

Spinal  anesthesia  with  cocaine  has  been  effective  in  protect- 
ing the  trunk  and  hind-limbs  of  animals  from  the  convulsions, 
but  it  does  not  protect  the  fore-limbs  and  head,  and  does  not 
prevent  the  great  relaxation  of  the  voluntary  muscles,  even  in 
the  hind-limbs. 

2.  Artificial  Respiration  and  the  Inhalation  of  Oyxgen. — The 
oxygen  acts  not  only  to  furnish  respiratory  oxygen,  which  is 
deficient  because  of  the  interference  with  respiration  and  of 
muscular  activity,  but  also  to  increase  the  rapidity  of  oxidation 
of  the  strychnine  in  the  body.  Gies  and  Meltzer  claim  that  the 
rhythmic  motions  of  artificial  respiration  tend  to  delay  the  onset 
of  convulsions. 

3.  Catheterization  of  the  bladder  to  remove  and  so  prevent 
reabsorption  of  the  strychnine  passed  out  by  the  kidneys. 

4.  Saline  Infusion. — Delbert  found  that  if  he  followed  the 
injection  of  a  lethal  dose  of  strychnine  into  a  dog  by  an  intrave- 
nous infusion  of  normal  saline,  free  diuresis  promptly  resulted  and 
no  signs  of  strychnine  poisoning  were  manifest. 

From  a  series  of  experiments  Githens  and  Meltzer  (191 2) 
recommend  the  combination  of  ether  anesthesia,  intratracheal 
insufflation,  and  intravenous  administration  of  Ringer's  solution. 

Therapeutics. — Strychnine  and  nux  vomica  preparations 
are  extensively  employed  as  tonics  in  conditions  of  debility  with 
loss  of  appetite,  and  in  convalescence  from  severe  illnesses.  In 
these  conditions  the  effect  on  appetite  is  of  value  as  well  as  that 
on  tone.  For  a  more  marked  action  on  the  reflexes,  they  are 
given  in  atonic  conditions  of  the  abdominal  viscera,  as  of  stomach, 
intestines,  bladder,  and  uterus,  in  the  relaxed  atonic  types  of 
chronic  bronchitis,  in  conditions  of  weak,  ineffective  cough, 
as  in  severe  tuberculosis  with  much  bronchial  secretion,  and  in 
acute  and  chronic  alcoholism. 

Further,  in  serious  acute  diseases  like  pneumonia,   where 


NUX   VOMICA  265 

there  is  much  prostration,  and  in  narcotic  poisoning,  as  from  alco- 
hol, ether,  or  chloral  hydrate,  large  doses  may  be  administered 
for  respiratory  and  spinal  stimulation.  It  is  to  be  noted  that 
while  strychnine  is  good  in  chloral  poisoning,  chloral  hydrate  is 
not  good  in  strychnine  poisoning. 

In  nervous  disease  strychnine  is  extensively  employed,  but 
its  use  requires  careful  discrimination.  Its  application  is  as 
follows : 

(a)  In  the  post-operative  paralysis  of  stomach  or  intestine 
the  drug  would  seem  to  be  the  best  that  we  have. 

(b)  In  paralysis  from  disease  of  the  anterior  horn  cells  (an- 
terior poliomyelitis,  progressive  muscular  atrophy,  amyotrophic 
lateral  sclerosis)  moderate  improvement  may  come  from  in- 
creased transmission  of  the  regular  afferent  impulses. 

(c)  In  lesions  involving  the  posterior  columns  of  the  cord 
(e.  g.,  locomotor  ataxia)  the  result  is  problematic.  Large  doses 
may  bring  about  improvement  in  some  of  the  functions,  but  often 
are  of  no  value  at  all. 

(d)  In  sexual  feebleness  without  evidence  of  an  organic 
lesion  the  effect  on  the  reflexes  may  be  of  value. 

(e)  In  paralysis  due  to  lesions  of  the  motor  area  of  the  brain, 
or  of  the  motor  tract  or  cord,  the  tendency  of  the  drug  is  harmful; 
for  the  reflexes  of  the  cord  below  the  lesion  are  cut  off  from  the 
normal  cerebral  control.  As  a  result,  they  are  so  heightened 
in  activity  that  they  approach  the  incoordinated  type.  The 
muscles  are  in  a  state  of  overtone,  and  in  voluntary  motion  the 
opposing  muscles  do  not  readily  relax;  so  it  requires  but  slight 
provocation  to  bring  the  limb  into  a  state  of  spasticity  or  rigidity, 
with  perhaps  clonic  contraction  of  the  muscles  (as  in  the  spastic 
gait).  Therefore  in  hemiplegia,  multiple  sclerosis,  transverse 
myelitis,  and  other  conditions  with  spastic  paralysis,  strychnine 
would  tend  to  increase  the  already  bad  condition.  The  writer 
found  a  man  with  multiple  sclerosis  who  was  being  given  two  pills 
of  aloin,  belladonna,  and  strychnine,  -^  grain  (0.001  gm.)  in  each 
three  times  a  day,  together  with  strychnine  sulphate,  -^  grain 
(0.002  gm.),  and  a  dose  of  Bright's  tonic,  containing  strychnine 
sulphate,  ^5-  grain  (0.001  gm.).  The  amount  of  strychnine 
sulphate  being  administered  was  thus  TV  grain  (0.005  &m-) 
three  times  a  day.  He  was  in  such  a  spastic  condition  that  he 
could  not  walk,  and  could  scarcely  use  his  hands  to  button  his 
clothes.  The  substitution  of  bromides  for  the  strychnine  re- 
sulted in  a  marked  improvement  in  two  days. 

(/)  In  diminished  vision,  whether  functional  or  from  retinitis 
or  partial  optic  nerve  atrophy,  large  doses  sometimes  give  good 
results.     In  these  cases  the  drug  may  be  given  internally  in  the 


266  PHARMACOLOGY   AND    THERAPEUTICS 

usual  way;  or,  if  the  eye  only  is  to  be  treated,  may  be  injected 
into  the  neighborhood  of  the  affected  eye,  or  even  in  i  per  cent, 
solution  dropped  into  the  eye. 

Contraindications. — Spasmodic  conditions  of  all  kinds,  as — (a) 
Of  smooth  muscle — spasmodic  asthma  and  biliary,  renal,  or  intes- 
tinal colic,  or  spastic  constipation;  (b)  of  voluntary  muscle — 
hiccup,  convulsive  tic,  epilepsy,  and  any  spastic  condition,  as 
from  a  lesion  involving  the  motor  area  or  tract. 

Administration. — For  a  bitter  effect,  the  tincture  of  nux 
vomica  is  preferred  (10  minims  =  y-g-g-  grain  of  strychnine,  or 
about  -g^o  grain  of  strychnine  sulphate).  It  is  given  about 
ten  minutes  before  meals,  diluted  with  water  to  make  a  bitter 
drink.  For  the  purposes  of  a  bitter  it  is  useless  if  given  in  cap- 
sules or  coated  pills.  For  a  tonic  effect  any  of  the  preparations 
may  be  employed,  the  strychnine  salts  being  frequently  pre- 
scribed by  themselves  in  the  form  of  tablet  triturates.  For 
hypodermatic  use,  the  strychnine  salts  alone  are  suitable. 


As  camphor  has  already  been  considered,  and  the  other 
central  stimulants,  atropine  and  cocaine,  are  at  the  same  time 
pronounced  peripheral  depressants,  we  shall  defer  their  consid- 
eration for  the  present. 


Remedies  Which  Depress  the  Central  Nervous  System 

—Narcotics 

As  the  remedies  which  depress  the  central  nervous  system 
regularly  depress  the  cerebrum,  they  are  known  generally  as 
narcotics,  a  narcotic  being  a  remedy  which  tends  to  produce  a 
depressed  state  of  consciousness.  Consciousness  is  a  function  of 
the  cerebral  cortex.  The  rapidity  of  the  onset  of  narcosis  varies 
greatly  with  the  different  narcotics,  but  the  degree  of  narcosis 
increases  in  a  regular  way  with  the  amount  given.  Slight 
narcosis,  for  example,  shows  merely  in  a  tendency  to  quietness, 
while  greater  degrees  show  in  succession  drowsiness  with  mental 
and  physical  sluggishness,  then  sleep,  not  quite  like  the  natural 
sleep,  then  stupor,  and  finally  loss  of  consciousness  (coma). 
Stupor,  or  torpor,  is  a  condition  of  unconsciousness  or  semicon- 
sciousness from  which  one  can  be  aroused,  but  with  difficulty; 
and  coma,  a  condition  of  unconsciousness  from  which  one  cannot 
be  aroused. 

The  classes  of  narcotics  are:  (i)  General  Anesthetics; 
(2)  Intoxicants;  (3)  Hypnotics;  (4)  Antihysterics. 


.ETHER  267 

General  Anesthetics 

The  ones  in  common  use  are:  Ether,  chloroform,  nitrous 
oxide,  and  ethyl  chloride. 

As  ether  and  chloroform  have  uses  in  therapeutics  which  do 
not  involve  the  production  of  general  anesthesia,  we  shall  first 
take  up  their  general  pharmacology  and  therapeutics,  and  after- 
ward their  special  uses  as  anesthetics. 

jETHER 

Ether,  or  ethyl  oxide,  (C2H5)oO,  is  obtained  by  distilling  a 
mixture  of  sulphuric  acid  and  alcohol.  It  is  a  very  volatile, 
light,  colorless,  limpid  liquid,  with  a  burning,  unpleasant  taste 
and  a  characteristic  penetrating  odor.  It  boils  at  about  35.50  C. 
(960  F.),  and  should,  therefore,  boil  when  a  test-tube  of  it  con- 
taining some  broken  glass  is  held  for  a  time  closely  grasped  in  the 
hand.  It  is  highly  inflammable,  and  its  vapor  mixed  with  air  is 
explosive.  It  mixes  freely  with  alcohol  and  chloroform,  and  is  a 
solvent  of  resins,  fats,  oils,  adhesive  plaster,  and  collodion.  In 
water  it  is  soluble  up  to  about  10  per  cent.  (U.  S.  P.)  (Moore  and 
Roaf  say  8  per  cent,  in  water  and  n  per  cent,  in  blood-serum). 
Its  chief  impurities  are  acids,  acetaldehyd,  and  peroxides.  Even 
in  originally  pure  specimens  these  impurities  may  develop  in  the 
presence  of  light  and  air.  They  are  removed  if  the  vapor  is 
passed  through  water. 

Preparations  and  Doses.— 

Ether  (aether),  by  mouth,  15  minims  (1  c.c). 
Spirit,  32.5  per  cent.,  1  dram  (4  c.c). 
Compound  spirit — Hoffmann's  anodyne  (ether,  32.5  per 
cent.;  and  ethereal  oil,  2.5  per  cent.),  1  dram  (4  c.c). 
This  has  a  sharp,  unpleasant  taste,  but  is  the  favorite 
preparation  for  stomach  administration. 

Pharmacologic  Action. — Ether  is  a  general  protoplasmic 
poison. 

Skin. — If  applied  to  the  skin  and  allowed  to  evaporate,  ether 
blanches  and  cools  the  part  by  its  rapid  evaporation;  if  it  is 
applied  in  the  form  of  a  fine  spray,  it  evaporates  so  rapidly  that 
the  part  is  numbed  by  the  cold  or  may  even  be  frozen.  If 
applied  to  the  skin  and  not  allowed  to  evaporate,  it  irritates  and 
is  rubefacient. 

Mucous  Membranes. — To  these  it  is  very  irritant,  so  for  ad- 
ministration by  stomach  it  requires  dilution  with  water,  and  for 
administration  by  the  lungs  it  requires  dilution  with  air  or 
oxygen. 

Alimentary  Tract. — It  has  a  burning,  unpleasant  taste,  irri- 
tates the  mouth,  and  induces  a  reflex  flow  of  saliva  and  mucus. 


268  PHARMACOLOGY  AND  THERAPEUTICS 

In  the  stomach,  if  given  undiluted,  it  burns  and  may  induce 
vomiting.  If  moderately  diluted,  it  is  carminative,  tending  to 
promote  the  expulsion  of  gas  and  to  relieve  with  great  promptness 
the  reflex  and  direct  effects  of  a  distended  stomach  upon  the 
heart,  the  diaphragm,  and  the  abdominal  contents.  It  also 
overcomes  colic.  As  it  is  so  volatile,  it  is  very  prompt  in  its 
action,  but  it  may  produce  eructations  of  ether-tasting  gas, 
especially  in  fever  or  if  given  with  hot  water. 

Absorption  is  very  rapid,  whether  the  administration  is  by 
stomach  or  rectum  or  lungs. 

Circulation. — From  local  irritation,  whether  from  inhalation 
or  swallowing,  there  is  a  prompt  but  momentary  reflex  stimula- 
tion of  the  heart's  rate  and  force  with  rise  in  arterial  pressure. 
This  is  due  probably  to  reflex  stimulation  of  the  accelerator 
center  and  reflex  stimulation  of  the  vasoconstrictor  center. 

Muehlberg  and  Kramer  have  shown  that  the  injection  of  a 
few  minims  of  undiluted  ether  into  the  carotid  artery  of  a  rabbit, 
so  that  it  passes  at  once  to  the  medullary  centers,  is  followed 
immediately  by  intense  stimulation  of  the  vagus  and  vasocon- 
strictor centers.  Thus  it  causes  vagus  weakening  of  the  heart, 
and  at  the  same  time  excessive  peripheral  resistance.  The 
result  is  stoppage  of  the  heart  in  a  condition  of  dilatation.  In 
laboratory  animals  death  in  this  manner  frequently  results  if  an 
overwhelming  amount  of  ether  is  administered  at  the  outset.  In 
man  no  such  deaths  are  reported,  and  this  may  be  because 
ether  is  so  irritant  that  it  needs  to  be  administered  gradually. 
For  it  is  found  that  if  the  administration  is  gradual,  whether  by 
inhalation,  by  rectum,  or  by  vein,  the  centers  become  narcotized 
so  that  they  are  resistant  to  the  irritant  effect.  In  careful  anes- 
thesia the  effect  upon  the  medullary  centers  is  very  little  if  any 
at  first,  but  after  a  time  they  become  depressed. 

The  heart  muscle  may  be  temporarily  stimulated,  as  it  tends 
to  be  by  protoplasmic  irritants,  but  after  a  time,  in  prolonged 
anesthesia,  or  if  overwhelming  amounts  of  ether  are  given,  it 
shows  weakening.  Loeb  found  that  when  the  perfusing  fluid 
contained  0.4  per  cent,  of  ether,  an  isolated  dog's  heart  stopped 
in  extreme  diastolic  relaxation.  ^ 

With  amounts  such  as  are  used  in  the  average  anesthesia 
there  may  be  a  rise  in  blood-pressure  for  the  first  fifteen  minutes, 
and  then  a  slight  lowering  to  the  normal  or  slightly  below  normal. 
The  rate  is  somewhat  increased,  and  there  is  marked  flushing  of 
the  skin  from  dilatation  of  the  cutaneous  arterioles. 

Blood. — In  a  test-tube,  2  per  cent,  of  ether  added  to  the 
blood  shows  a  tendency  to  destroy  the  red  cells  and  to  precipitate 
hemoglobin.     Yet,  as  administered  to  man,  ether  does  not  reach 


AETHER  269 

this  concentration,  and  does  not  seem  to  interfere  with  the 
oxygen-carrying  power  of  the  blood.  For  other  reasons,  however, 
surgeons  hesitate  to  employ  ether  anesthesia  for  persons  with 
hemoglobin  below  about  50  per  cent. 

Respiration. — The  reflex  stimulation  from  mouth,  stomach, 
or  respiratory  passages  extends  to  the  respiratory  center,  and 
breathing  is  at  first  quickened  and  deepened.  Henderson 
thinks  that  this,  with  the  resistance  in  the  first  stages  of  anes- 
thesia, is  a  possible  cause  of  acapnia.  (See  Shock.)  After 
absorption,  ordinary  amounts  have  little  effect;  but  large  amounts, 
as  in  anesthesia,  tend  to  depress  the  center.  The  usual  cause  of 
death  is  asphyxia  from  respiratory  paralysis.  In  experiments 
with  very  dilute  ether  the  respiration  regularly  fails  before  the 
heart,  though  the  latter  is  very  weak  and  interferes  with  restitu- 
tion. 

Nervous  System. — Like  other  strong  carminatives,  ether 
tends  to  overcome  hysteric  conditions  and  states  of  nervous 
instability.  It  probably  acts  reflexly  from  the  stomach  as  a 
cerebral  stimulant,  promoting  the  control  of  the  highest  centers. 

After  absorption  it  acts  as  a  direct  cerebral  depressant  or 
sedative,  depressing  the  intellectual  centers  and  the  motor  areas. 
Hence  small  amounts  may  be  hypnotic,  and  large  amounts  will 
induce  coma,  as  in  anesthesia. 

For  the  nervous  structures  themselves  it  has  a  special  affinity, 
and  after  an  ether  death  more  ether  is  found  in  the  brain  than  in 
any  other  organ.  There  are  several  theories  to  account  for  this 
accumulation  in  the  central  nervous  system,  and  the  production 
of  narcosis  by  ether,  chloroform,  and  similar  substances.  We 
shall  speak  of  them  later. 

In  poisoning  by  ether  there  is  a  progressive  depression  of  the 
central  nervous  system.  The  higher  cerebral  functions,  those 
involving  intellectual  processes,  as  self-control,  judgment,  and 
reason,  are  the  first  to  succumb,  so  that  the  emotions  are  freed 
from  control.  Then  the  emotions,  the  perceptions,  the  motor 
functions,  and  coordination  by  the  cerebellum  are  depressed. 
Then  there  is  abolition  of  the  spinal  reflexes,  and  finally  depres- 
sion of  the  vital  medullary  centers.  Sensory  centers  are  affected 
before  motor,  so  complete  insensitiveness  to  the  surroundings 
and  to  pain,  i.  e.,  complete  abolition  of  the  perceptions,  precedes 
complete  muscular  relaxation.  The  action  of  ether  upon  the 
brain  and  spinal  cord  is  directly  antagonistic  to  that  of  strychnine 
and  caffeine.  The  sensory  nerve-endings  are  also  somewhat 
depressed. 

Eye. — As  affected  in  the  production  of  anesthesia,  the  pupil 
is  at  first  dilated  reflexly,  either  from  excitement,  from  irritation 


270  PHARMACOLOGY  AND  THERAPEUTICS 

of  the  nose  and  throat,  or  from  pain.  It  has  the  usual  sensi- 
tiveness to  light.  In  the  stage  of  stupor  it  contracts  as  in  sleep, 
and  is  still  quite  sensitive  to  light.  In  the  stage  of  complete 
anesthesia  it  is  in  mid-dilatation  (Hewitt  says  3.5  to  4.5  mm.  in 
diameter) ,  and  almost  insensitive  to  light.  This  is  due  to  depres- 
sion of  the  third  nerve  center,  which  in  the  light  reflex  controls 
the  constrictor  muscle  of  the  iris.  In  the  stage  of  collapse  the 
pupil  is  dilated  and  insensitive  to  light,  owing  to  the  paralysis  of 
this  center. 

Muscle. — In  perfusion  of  a  limb  there  is  no  weakening  of 
the  muscle  unless  the  ether  concentration  is  high. 

Temperature. — From  large  doses  the  temperature  tends  to 
fall,  both  because  of  a  striking  diminution  in  the  production  of 
heat  on  account  of  the  diminished  muscular  activity  and  loss  of 
tone,  and  of  increased  dissipation  of  heat  through  wide  dilatation 
of  the  cutaneous  vessels  and  sweating.  The  fall  in  temperature 
will  be  increased  by  exposure  during  an  operation. 

Elimination  is  rapid  and  essentially  by  the  lungs;  it  is  prob- 
able that  in  prolonged  anesthesia  some  passes  out  in  the  urine. 

Kidneys. — During  anesthesia  there  is  inhibition  of  urine 
formation,  owing  to  contraction  of  the  arterioles;  after  the  anes- 
thesia there  is  diuresis  (Hawk).  After  anesthesia,  albuminuria 
is  frequently  noticed,  perhaps  in  one-fourth  of  the  cases,  the 
statistics  in  published  reports  varying  from  5  to  36  per  cent. 
The  condition  is  usually  transitory,  but  occasionally  it  goes  on 
to  an  acute  nephritis,  with  albumin  and  blood  in  the  urine.  This 
would  seem  to  indicate  direct  irritation  of  the  kidney-cells  by 
the  ether,  but  it  is  a  result  that  may  be  due  solely  to  the  local 
contraction  of  the  renal  vessels  or  to  partial  asphyxia.  (Accord- 
ing to  Fischer's  theory,  191 1,  it  may  be  due  to  acidosis.)  Acetone 
is  also  frequently  found  in  the  urine  for  one  or  two  days  after 
ether  anesthesia. 

Skin. — From  moderate  doses  there  are  flushing  of  face  and 
neck  and  a  tendency  to  sweating.  From  anesthetic  amounts 
there  is  usually  flushing  of  the  whole  skin  with  profuse  sweating; 
and  sometimes  mottling  of  the  skin  or  a  general  erythema  of 
transitory  nature — the  so-called  "ether  rash." 

The  ether  habit  is  sometimes  encountered,  the  devotee  inhal- 
ing frequently  through  the  nostrils  or  swallowing  the  diluted 
drug. 

Therapeutics  of  Ether.— When  not  employed  as  a  general 
anesthetic. 

Externally.— It  is  used  to  cleanse  the  skin,  preparatory  to 
operations,  small  or  large. 

Internally. — It  is  employed  in  the  form  of  Hoffmann's  anodyne. 


CHLOROFORM  27 1 

Though  the  taste  is  rank  and  unpleasant,  this  is  one  of  our  most 
powerful  carminatives.     On  account  of  the  volatility,  eructa- 
tions may  keep  bringing  this  taste  back  into  the  mouth. 
The  therapeutic  uses  of  Hoffmann's  anodyne  are: 

1.  As  carminative  and  reflex  stimulant — in  flatulence,  and  espe- 
cially in  faintness  or  fainting  following  distention  of  the  stomach. 

2.  To  relieve  angina  pectoris  and  allied  cardiac  disturbances. 
It  acts  by  relieving  stomach  distention  and  by  its  reflex  effect 
upon  the  circulation. 

j.  To  relieve  dyspnea  (bronchial,  cardiac,  or  that  due  to  a 
much-distended  stomach). 

4.  To  relieve  spasm — as  in  intestinal  colic,  spasmodic  asthma, 
and  hiccup. 

5.  To  allay  hysteria  and  states  of  nervous  instability. 
Because  of  the  bad  taste  and  eructations  it  is  sometimes 

mixed  with  ichthyol  and  the  tinctures  of  valerian  and  asafetida 
to  form  the  "bum  mixture,"  a  preparation  which  is  given  to 
hospital  bums  when  they  come  in  on  various  pretexts  of  illness 
merely  to  get  a  bed  and  meals.  The  repeated  gas  eructations 
caused  by  the  ether  keep  the  taste  of  this  mixture  in  the  mouth, 
and  the  result  is  the  willing  departure  of  the  patient  from  the 
hospital. 

CHLOROFORM 

Chloroform  (chlorof ormum) ,  CHC13,  is  a  non-inflammable, 
volatile  liquid,  which  is  about  i}4  times  as  heavy  as  water, 
boils  at  1410  F.,  and  has  a  burning,  strikingly  sweetish  taste. 
It  mixes  freely  with  alcohol,  ether,  and  the  oils,  and  dissolves  to 
the  extent  of  about  0.5  per  cent,  in  water  (U.  S.  P.).  Moore  and 
Roaf  found  it  to  be  soluble  to  the  extent  of  0.95  per  cent,  in  water, 
and  to  the  extent  of  4  per  cent,  in  blood-serum,  and  their  work 
indicated  that  this  extra  solubility  in  serum  was  due  to  the  forma- 
tion of  a  loose  protein  compound. 

On  long  standing,  or  if  exposed  to  sunlight  or  a  flame,  chloro- 
form may  decompose,  with  the  formation  of  free  hydrochloric 
acid,  or  the  poisonous  carbonyl  chloride  (COCl2) ,  or  free  chlorine, 
which  is  very  irritating.  Alcohol  acts  as  a  preservative,  as  the 
chloroform  does  not  undergo  decomposition  so  long  as  there  is 
any  alcohol  present  to  be  oxidized.  Hence  the  Pharmacopoeia 
specifies  that  0.6-1  per  cent,  of  alcohol  shall  be  present. 
Preparations  and  Doses.— 

Chloroform,  5  minims  (0.3  ex.). 

Water  i}/2  per  cent.),  4  drams  (15  c.c). 

Emulsion  (4  per  cent.),  2  drams  (8  c.c). 

Spirit  (6  per  cent.),  30  minims  (2  c.c). 

Liniment — (chloroform,  30  per  cent.,  soap  liniment,  70  per 
cent.). 


272  PHARMACOLOGY   AND   THERAPEUTICS 

Pharmacologic  Action. — Chloroform  is  a  general  proto- 
plasmic poison  of  considerable  destructive  power.  If  concen- 
trated, it  will  cause  the  death  of  tissues  with  which  it  comes  in 
contact;  and  even  when  dilute,  as  in  the  blood,  it  can  readily 
produce  degenerative  changes  in  various  organs  of  the  body. 
This  striking  property  seems  to  be  common  to  various  hydro- 
carbons which  contain  chlorine. 

Microorganisms. — Chloroform  is  antiseptic,  and  even  in  such 
a  dilute  solution  as  "chloroform  water"  {y2  per  cent,  in  strength) 
will  retard  putrefaction  and  fermentation,  as  in  urine. 

Local. — It  is  less  volatile  than  ether,  so  is  less  cooling  to  the 
skin,  and  its  tendency  is  rather  to  irritate  than  to  soothe.  If  it 
is  dropped  on  the  face  from  a  chloroform  inhaler  and  prevented 
from  ready  evaporation,  it  will  make  a  decided  burn.  In  lini- 
ments, if  evaporation  is  prevented  by  covering  with  flannel  or 
oiled  silk,  it  is  counterirritant. 

Alimentary  Tract. — Undiluted,  it  is  very  irritating  to  throat 
and  stomach;  but  its  official  preparations,  being  very  dilute,  are 
sweet  to  the  taste  and  pleasant  carminatives.  They  are  also 
soothing  to  the  stomach  and  antemetic.  It  is  said  that  the 
activity  of  rennet  and  pepsin  is  promoted  by  solutions  of  less  than 
0.5  per  cent,  strength,  and  retarded  by  strong  solutions. 

Heart. — In  perfusing  an  isolated  heart,  the  addition  of  a 
small  amount  of  chloroform  results  in  a  momentary  strengthen- 
ing, followed  very  quickly  by  muscular  weakness,  the  heart  soon 
becoming  dilated  and  the  beats  small  and  ineffective.  The  drug 
is  a  strong  poison  to  cardiac  muscle.  Sherrington  and  Sowton 
found  that  in  a  perfusion  fluid  a  strength  of  0.05  per  cent,  of 
chloroform  was  sufficient  regularly  to  arrest  the  heart,  but  that 
restoration  would  take  place  on  returning  to  pure  saline.  That 
is,  when  the  osmotic  pressure  of  chloroform  in  the  cardiac  cells  is 
below  a  certain  limit,  the  heart  beats  again.  If  too  strong 
chloroform  is  used,  the  heart  cannot  dissociate  itself  from  the 
chloroform  and  death  ensues. 

Levy  and  Lewis  (191 2),  experimenting  with  cats,  found  that 
light  anesthesia,  i.  e.,  with  the  tension  of  chloroform  vapor  in  the 
inspired  air  between  0.5  and  1.5  per  cent.,  regularly  produced 
irregularities  in  the  action  of  the  ventricle,  of  the  types  described 
under  "Digitalis "  as  due  to  excessive  irritability.  They  observed 
paroxysmal  tachycardia  (of  ventricular  origin),  premature  ven- 
tricular contractions,  and  ventricular  fibrillation.  The  increase 
of  the  vapor  tension  to  2  per  cent,  was  regularly  followed  by  the 
disappearance  of  the  irregularity. 

With  the  low-tension  vapor,  a  small  intravenous  of  epi- 
nephrine chloride  produced  the  worst  form  of  irritability,  viz., 


***** 


Aur. 


Ven. 


B.  P. 


Fig.  36. — Chloroform,  10  breaths,  (b)  diminished  the  contractility  of  both 
auricle  and  ventricle,  and  caused  a  fall  in  blood-pressure  from  76  to  56  mm.  Caf- 
feine, 5  mg.  per  kilo,  (a)  resulted  in  increased  contractility  of  auricle  and  ventricle 
(down-stroke),  and  a  rise  in  blood-pressure  from  68  to  82  mm.  The  effect  was 
somewhat  lasting.     (Tracing  made  by  Dr.  C.  C.  Lieb.) 


CHLOROFORM  273 

ventricular  fibrillation,  which  usually  means  immediate  death; 
with  the  higher  tension  vapor  a  small  intravenous  of  epinephrine 
produced  the  irregularities  which  had  been  observed  to  result 
from  the  low  percentages  of  chloroform  alone. 

Of  considerable  importance  in  anesthesia  is  the  finding  of 
Cushny  and  Edmunds  that  the  heart  may  be  dilated  and  very 
weak  before  there  is  any  noteworthy  change  in  its  rate. 

Arteries. — On  passing  chloroformized  blood  to  the  cerebral 
circulation  without  letting  it  get  into  the  general  circulation  (i.  e., 
by  a  crossed  circulation  between  two  animals) ,  there  is  a  momen- 
tary rise  in  arterial  pressure,  followed  quickly  by  a  fall;  that  is, 
the  vasoconstrictor  center,  after  a  primary  irritation,  is  depressed. 
Bayliss,  who  has  done  much  work  on  inhibition,  thinks  that  the 
vasoconstrictor  center  is  changed  by  chloroform  so  that  affer- 
ent impulses,  which  normally  result  in  vasoconstriction,  now 
result  in  vasodilatation.  (See  Sherrington's  theory  under 
Strychnine.) 

In  some  cases  the  destructive  action  results  in  fatty  degenera- 
tion of  the  heart,  the  cardiac  ganglia,  and  even  the  arteries.  This 
is  particularly  likely  to  be  the  case  after  the  prolonged  admin- 
istration of  chloroform  for  anesthesia,  or  the  repetition  of  its 
administration  as  an  anesthetic  within  a  day  or  two.  In  anes- 
thesia, death  sometimes  takes  place  from  collapse,  due  to  depres- 
sion of  the  heart  and  arterial  muscles  or  to  ventricular  fibrilla- 
tion. In  the  early  stages  of  the  anesthesia,  before  the  patient 
is  fully  anesthetized,  death  may  be  due  to  powerful  reflex  stimu- 
lation of  the  vagus  and  vasoconstrictor  centers,  the  latter  caus- 
ing abnormal  peripheral  resistance  against  a  weakened  heart. 
Muehlberg  and  Kramer,  by  the  injection  of  a  few  minims  of 
chloroform  into  the  carotid  artery  or  jugular  vein  of  laboratory 
animals,  obtained  intense  stimulation  of  the  vagus  and  vaso- 
constrictor centers  with  heart  failure. 

Respiratory. — There  is  a  decided  depression  of  the  respiratory 
center,  preceded  by  a  very  short  period  of  stimulation.  In  some 
cases  respiratory  paralysis  is  the  cause  of  death,  and  in  experi- 
ments with  the  much  diluted  vapor  the  respiration  regularly 
ceases  before  the  heart;  but  the  heart  is  too  weak  to  permit 
resuscitation.  In  the  throat  and  bronchi,  if  the  vapor  is  prop- 
erly diluted,  it  is  not  irritating  and  may  even  be  soothing,  so  that 
cough  or  bronchial  irritation  may  be  less  after  the  anesthesia  than 
before  (Bennett). 

Nervous  System. — The  effects  are  practically  those  of  ether, 

the   cerebral   and  spinal   depression,   however,    following   more 

rapidly  and  from  a  much  smaller  amount  of  drug.     The  highest 

intellectual  functions  are  depressed  first,   then,  in  succession, 

18 


274  PHARMACOLOGY   AND   THERAPEUTICS 

the  emotional  and  motor,  the  cerebellar,  the  spinal,  and  finally 
the  medullary.  By  removing  the  pia  from  a  portion  of  the  cord 
to  exclude  that  portion  from  the  action  of  the  drug,  Bernstein 
tried  to  find  the  exact  site  of  action  of  chloroform.  On  lightly 
anesthetizing  the  animal  he  found  that  on  irritating  the  afferent 
nerves  whose  cells  were  in  the  excluded  area  reflexes  could  be 
obtained  involving  motor  cells  in  the  chloroformized  parts  of 
the  cord,  i.  e.,  the  motor  cells  were  not  paralyzed.  But  on 
irritating  the  afferent  nerves  whose  fibers  passed  through  the 
chloroformized  part  of  the  cord,  there  was  no  motor  response  at 
all.  Therefore,  he  concluded,  the  action  of  chloroform  must 
be  on  the  first  synapse  or  the  intermediate  neuron  of  the  afferent 
system,  the  same  structure,  probably,  that  is  excited  by  strych- 
nine. (See  Fig.  35.)  With  larger  amounts  of  chloroform  the 
motor  cells  or  their  synapses  are  also  paralyzed. 

Eye. — In  complete  anesthesia  the  pupil  is  rather  contracted, 
and  of  about  1.5  to  3  mm.  in  diameter,  i.  e.,  two-thirds  the  diam- 
eter of  the  ether  pupil. 

Elimination  is  chiefly  by  the  lungs  and  is  rapid.  Traces  are 
also  found  in  the  urine;  also  in  milk  and  fetal  blood. 

Kidneys. — Figures  as  to  the  occurrence  of  albuminuria  after 
ether  and  chloroform  vary  considerably  with  the  different  writers. 
After  41  ether  anesthesias  Babaci  and  Bebi  noted  albuminuria  in 
36  per  cent. ;  while  after  54  chloroform  anesthesias,  albuminuria 
occurred  in  only  18  per  cent.,  i.  e.,  ether  proved  twice  as  likely 
to  produce  albuminuria  as  chloroform.  On  following  up  their 
observations  with  experiments  on  dogs,  guinea-pigs,  and  rabbits, 
these  investigators  found  that  though  ether  more  readily  causes  a 
passing  or  functional  albuminuria,  chloroform  is  more  prone  to 
produce  destructive  changes,  i.  e.,  fatty  degeneration  and  per- 
manent inflammatory  lesions.  Hence  chloroform,  though  less 
prone  to  produce  albuminuria,  is  more  dangerous  to  the  kidneys 
than  ether. 

Metabolism. — Chloroform  tends  to  produce  fatty  changes  in 
various  organs,  in  the  following  order  of  extent  and  frequency: 
liver,  kidneys,  spleen,  heart,  arteries,  and  cardiac  ganglia,  and 
perhaps  the  lungs. 

The  main  effects  on  metabolism  are  due  to  the  marked  de- 
structive changes  in  the  liver.  There  is  a  decrease  in  the  storage 
of  glycogen,  and,  as  a  consequence,  an  increase  of  sugar  in  the 
blood.  In  the  urine  there  is  increase  in  phosphates,  chlorides, 
sulphates,  and  total  nitrogen,  the  ammonia  nitrogen  being  in- 
creased while  the  urea  is  decreased.  The  urine  sometimes  con- 
tains sugar,  acetone,  and  allied  bodies,  and  cystin,  leucin,  or 


CHLOROFORM  275 

tyrosin.  These  effects  are  evidences  of  increased  destructive 
metabolism  with  incomplete  oxidation. 

Therapeutics  of  Chloroform,  Aside  From  its  Use  as  Anes- 
thetic.— Externally. — (i)  In  liniments,  as  a  rubefacient  for  mus- 
cular, joint,  and  neuralgic  pains.  (2)  On  cotton  in  a  decayed 
tooth  for  toothache. 

Internally. — (1)  As  a  mild  and  pleasant  carminative  in  flatu- 
lence or  colic — the  water  or  spirit.  (2)  As  an  antemetic  in  re- 
fractory cases  of  vomiting — one  dram  of  the  water  every  hour. 
(3)  As  antihysteric  and  cerebral  sedative — the  spirit. 

The  Chloroform  habit  is  not  uncommon,  the  sweet  taste  and 
narcotic  action  making  the  drug  a  rather  pleasant  dose.  The 
effects  of  the  habit  are  similar  to  those  of  the  chloral  habit. 
(See  Chloral  Hydrate.) 

Narcosis  Theories. — There  are  several  theories  as  to  the 
manner  in  which  narcotic  drugs  reach  the  cerebral  cell  contents, 
and  as  to  how  they  act  to  produce  anesthesia.  The  best  known 
are: 

1.  The  Meyer-Over  ton,  which  was  propounded  by  Meyer  and 
Overton  independently.  It  is  that  these  drugs  exert  their  main 
action  on  the  central  nervous  system,  because  they  are  taken 
up  by  the  fats  and  lipoids  which  abound  there,  and  so  are  held  in 
considerable  amount  in  contact  with  the  cell-structures.  The 
lipoids  are  lecithin,  cholesterin,  cerebrin,  protagon,  etc.  Accord- 
ing to  these  authors,  the  anesthetic  property  increases  with  the 
solubility  in  fats  and  lipoids  and  the  insolubility  in  water.  The 
relation  of  the  activity  of  hypnotics  and  anesthetics  to  their 
solubility  in  lipoids  is  certainly  a  striking  one,  and  there  is  a 
very  large  amount  of  evidence  supporting  this  theory,  which  is 
the  one  most  generally  accepted.  It,  of  course,  merely  indicates 
how  the  anesthetic  gets  to  the  nerve-cell,  and  not  what  takes 
place  in  the  cell. 

2.  The  Theory  of  Moore  and  Roaf. — They  believe  that  nar- 
cosis or  anesthesia  is  due  to  a  change  in  the  protoplasm  of  the 
cerebral  cells  by  the  formation  of  loose  compounds  of  ether, 
chloroform,  etc.,  with  the  cell  proteins,  and  that  this  results  in 
limitation  of  the  activities  of  the  cerebral  protoplasm.  On 
account  of  the  instability  of  the  compounds,  these  remain  formed 
only  so  long  as  the  vapor-pressure  of  the  anesthetic  in  the  blood 
is  maintained;  so  on  stopping  the  administration  of  the  anes- 
thetic the  narcosis  soon  ceases.  In  the  words  of  Moore  and 
Roaf,  that  "a  certain  amount  of  the  anesthetic  will  be  taken  up 
by  the  lipoid  in  a  physical  fashion  there  can  be  no  doubt,  because 
of  the  high  solubility  of  these  anesthetics  in  such  lipoid  substances. 
But  we  hold  that  the  portion  of  the  anesthetic  so  taken  up  and 


276  PHARMACOLOGY  AND   THERAPEUTICS 

held  by  the  lipoid  is  passive  and  not  active,  and  that  it  is  the 
portion  taken  up  by  the  protein  which  is  active  in  paralyzing 
protoplasmic  activity  and  producing  anesthesia.  It  is  a  matter 
of  common  knowledge  that  the  greater  the  amount  of  fatty 
tissue  in  a  subject  undergoing  anesthetization,  the  greater  is 
the  amount  of  anesthetic  required.  The  portion  of  anesthetic 
absorbed  by  the  lipoid  is  imprisoned,  and  more  anesthetic  must 
be  given  in  order  to  raise  the  (vapor)  pressure  of  the  anesthetic 
sufficiently  to  cause  combination  between  cell-protoplasm  and 
anesthetic,  with  resulting  anesthetization." 

The  one  theory  assumes  that  the  ether  dissolved  in  the  fats 
and  lipoids  is  the  anesthetic  ether;  the  other  considers  this  ether 
lost  or  imprisoned,  and  the  anesthetic  ether  to  be  only  that  which 
enters  into  combination  with  the  cell  proteins. 

3.  That  of  Verwom. — He  accepts  the  Meyer-Overton  theory 
as  showing  the  properties  necessary  for  an  anesthetic  to  reach 
the  field  of  action.  But  he  goes  on  to  give  an  explanation  of  the 
cause  of  the  depression  of  the  activity  of  the  cerebral  cells.  He 
shows  that  in  narcosis  there  is  interference  with  the  oxidative 
processes  of  the  cells,  or,  in  his  own  words,  ''the  factor  which 
produces  the  characteristic  symptom-complex  of  narcosis  is 
under  all  circumstances  the  suppression  of  the  power  to  carry  on 
oxidations."  His  theory  is  that  narcotics  render  the  oxidases 
(the  oxygen  carriers)  in  living  tissues  incapable  of  carrying 
oxygen.  He  shows  that  this  may  take  place  in  any  cells  of  the 
body,  but  that  the  cells  of  the  cerebral  cortex  are  especially  sen- 
sitive to  lack  of  oxygen,  and  are  depressed  with  very  much  less  of 
the  narcotic  than  is  necessary  to  depress  the  nerves  and  muscles. 

One  of  his  experiments  may  be  cited:  The  sciatic  nerve  of  a 
frog  was  deprived  of  oxygen  until  its  irritability  was  much  reduced 
and  its  conductivity  lost.  It  was  then  narcotized  with  ether. 
During  the  ether,  oxygen  was  supplied  for  a  long  time,  but  it  had 
no  effect  whatever  upon  the  narcosis.  Then  nitrogen  was  sub- 
stituted for  the  oxygen,  and  the  narcotic  was  stopped.  Still, 
though  the  ether  passed  off,  the  functions  were  not  restored  in 
the  nitrogen  atmosphere.  After  a  while  the  nitrogen  was  re- 
placed by  air,  and  in  one  minute  the  nerve  had  recovered  its 
conductivity  and  its  irritability.  That  is,  so  long  as  the  cell  was 
under  the  narcotic  influence,  oxygen  had  no  power  to  set  the  cell 
functionating,  but  did  set  it  functionating  when  the  narcotic  had 
been  removed.  Also  the  mere  removal  of  the  narcotic  was  not 
enough,  but  oxygen  was  necessary  to  restore  the  lost  functions 
of  the  cell. 


ETHER   AND    CHLOROFORM    AS    GENERAL   ANESTHETICS       277 

ETHER  AND  CHLOROFORM  AS  GENERAL  ANESTHETICS 

When  one  of  these  drugs  is  administered  in  sufficient  amount 
to  put  the  patient  into  a  state  of  coma,  with  muscular  relaxation 
and  the  abolition  of  nearly  all  reflexes,  the  patient  is  in  a  condi- 
tion of  "  complete  general  anesthesia."  The  study  of  general 
anesthesia  is,  then,  a  study  in  toxicology;  and  the  production  of 
ether  or  chloroform  anesthesia  is  the  production  of  acute  ether 
or  chloroform  poisoning,  the  patient  being  drugged  into  a  state 
of  narcosis  bordering  on  collapse. 

The  objects  of  general  anesthesia  are:  to  abolish  pain,  con- 
sciousness, and  muscular  resistance.  To  be  useful  as  a  general 
anesthetic,  a  drug  must  be  very  rapidly  absorbable,  must  act 
quickly  to  produce  narcosis,  and  must  be  very  rapidly  eliminated; 
and  it  must  be  capable  of  producing  muscular  relaxation  as  well 
as  complete  unconsciousness,  i.  e.,  abolishing  cerebral  and  spinal 
activity,  without  dangerous  depression  of  the  vital  medullary 
centers  or  any  permanent  effect  upon  the  central  nervous  system. 

As  these  drugs  are  highly  volatile  and  their  vapor  is  rapidly 
absorbed  by  the  lungs,  their  administration  by  inhalation  is 
preferred  as  being  more  controllable  and  more  easily  continued 
for  a  long  time;  but  a  sufficient  dose  by  mouth  or  rectum  or  vein 
will  also  produce  anesthesia. 

We  shall  take  up  ether  anesthesia  first,  then  compare  chloro- 
form anesthesia  with  it. 

For  general  anesthesia,  ether  is  regularly  administered  by 
inhalation,  the  vapor  being  diluted  with  air  or  oxygen  and  ab- 
sorbed by  the  lungs.  To  avoid  dangerous  irritation  of  the 
respiratory  passages  and  to  prevent  asphyxia,  the  ether  vapor 
must  not  constitute  more  than  a  small  percentage  of  the  total 
ether-air  mixture;  i.  e.,  it  must  be  diluted  with  air  for  administra- 
tion by  the  lungs,  just  as  Hoffmann's  anodyne  must  be  diluted 
with  water  for  administration  by  the  stomach.  To  get  the 
patient  quickly  into  a  condition  of  anesthesia  it  is  necessary 
that  the  air-ether  mixture  shall  contain  from  4  to  6  per  cent,  of 
ether;  while  to  maintain  the  anesthesia  it  must  be  kept  of  about  3 
to  3.5  per  cent,  strength.  It  is  unsafe  to  use  ether  in  a  strength 
above  4  per  cent,  for  any  great  length  of  time.  With  a  proper 
adjustment  of  the  amount  of  air  and  the  amount  of  ether  a 
patient  may  generally  be  kept  anesthetized  for  a  long  period, 
even  for  three  or  four  hours,  without  any  serious  symptoms 
manifesting  themselves. 

For  convenience  of  study  the  production  of  ether  anesthesia 
may  be  divided  into  four  stages: 

1.  Local  action  and  blunted  perceptions. 


278  PHARMACOLOGY  AND   THERAPEUTICS 

2.  Intoxication. 

3.  Stupor,  or  partial  surgical  anesthesia. 

4.  Coma  and  muscular  relaxation  or  complete  surgical 
anesthesia. 

Beyond  this  stage  we  get  collapse,  and  finally  death,  a  highly 
regrettable  outcome  of  our  voluntary  poisoning. 

It  must  be  borne  in  mind  that  there  is  no  sharp  line  of  demar- 
cation between  these  several  stages,  and  that  some  of  the  symp- 
toms of  one  stage  may  occur  with  some  of  the  symptoms  of 
another  stage.  The  division  into  stages  is  arbitrary,  and  is 
purely  for  convenience  of  study. 

The  First  Stage. — This  is  characterized  by  local  irritation, 
followed  by  local  numbness  and  blunted  senses. 

1.  Subjective  Symptoms. — The  ether  vapor  causes  irritation  of 
nose,  throat,  and  bronchi,  producing  a  sensation  of  choking  or 
lack  of  air  and  a  tendency  to  cough.  Soon  the  lips,  throat,  and 
nose  become  numb,  there  is  ringing  in  the  ears,  and  the  percep- 
tions become  dulled,  so  that  voices  sound  rather  distant  and  only 
things  close  by  are  noticed ;  but  the  patient  can  answer  questions 
and  may  talk.  As  he  loses  consciousness  he  feels  as  if,  no  matter 
what  happens,  he  is  powerless  to  lift  even  a  finger  to  help  himself; 
but  he  is  in  a  dreamy,  resigned  state,  and  doesn't  really  care  what 
does  happen. 

2.  Objective  Symptoms.— The  skin  soon  becomes  warm  and 
flushed,  the  pupils  are  dilated  from  excitement  or  from  irritation 
of  the  nose  and  throat,  the  heart  is  rapid,  and  arterial  pressure 
is  raised  from  the  reflex  stimulation  of  the  vasoconstrictor  center. 
Respiration  is  also  reflexly  stimulated,  but,  because  of  the  cough 
and  the  irritation  of  the  respiratory  tract,  there  is  involuntary 
resistance  to  breathing,  hence  it  is  irregular. 

The  second  stage  is  characterized  by  intoxication,  or  drunk- 
enness, similar  to  that  from  alcohol.  The  highest  centers  of 
the  cerebrum, — those  which  exert  judgment,  self-restraint,  etc., — 
the  intellectual  centers,  are  depressed,  and  the  emotional  and 
the  lower  animal  tendencies  are  more  or  less  freed  from  the 
normal  intellectual  control.  So  the  patient  is  childish,  or  may 
sing,  or  shout,  or  rave,  or  swear.  He  may  push  away  the  inhaler, 
or  try  to  get  up.  He  may  repeat  over  and  over  something  that 
the  doctor  has  said,  and  may  make  ugly  comments  on  the  char- 
acters of  his  attendants — in  fact,  he  is  drunk.  Though  his 
perceptions  are  dulled,  he  is  still  sensitive  to  pain.  On  recovery 
from  the  anesthesia  he  has  no  memory  of  this  stage. 

The  skin  is  flushed  and  may  show  an  ether  rash;  and  because 
of  the  resistance  to  respiration  and  the  necessity  at  this  stage  of 
giving  rather  concentrated  vapor,  it  may  become  somewhat 


ETHER  AND  CHLOROFORM  AS  GENERAL  ANESTHETICS   279 

cyanotic.  If  the  stomach  contains  food,  there  may  be  vomiting. 
The  pupils  are  dilated  and  react  to  light,  and  there  may  be  rolling 
of  the  eyeballs  or  strabismus,  with  the  eyelids  wide  open.  The 
heart  continues  somewhat  rapid  and  there  may  be  raised  blood- 
pressure.  If  the  patient  is  an  alcoholic,  very  fat,  or  robust  and 
athletic,  this  stage  is  rather  prolonged;  and  a  very  large  amount 
of  ether,  or  a  vapor  concentrated  even  up  to  10  per  cent.,  or  the 
addition  of  chloroform,  may  be  required  to  complete  the  anes- 
thesia. 

The  third  stage  is  that  of  stupor,  i.  e.,  unconsciousness  from 
which  one  can  be  aroused  only  with  difficulty.  The  pupils  are 
contracted  as  in  sleep,  the  heart  is  strong  and  regular  and  slower 
than  before  (though  not  slower  than  normal),  the  breathing  is 
deep  and  regular,  the  color  of  the  skin  is  good. 

The  intoxication  stage  is  over,  but  there  is  not  complete 
anesthesia,  for  if  the  knife  is  used  in  this  stage,  the  patient  will 
wince,  or  may  be  aroused  by  the  pain  and  try  to  get  up.  The 
muscular  relaxation  is  also  incomplete.  The  pupil  dilates  with 
pain  and  contracts  readily  to  light.  The  patient  may  be  kept  in 
this  stage  for  any  length  of  time,  or  may  quickly  be  brought 
into — 

The  fourth  stage,  which  is  characterized  by  great  muscular 
relaxation  and  complete  unconsciousness,  from  which  the  patient 
cannot  be  aroused,  i.  e.,  coma. 

Most  of  the  voluntary  muscles  are  relaxed.  An  arm  or  a  leg 
raised  in  the  air  falls  limp,  and  the  face  is  expressionless  from 
relaxation  of  the  face  muscles.  The  sphincter  ani  is  one  of  the 
last  of  the  voluntary  muscles  to  be  paralyzed.  The  respiratory 
muscles,  of  course,  are  not  paralyzed.  Smooth  muscle  loses  its 
tone  less  readily  than  voluntary  muscle,  and  intestinal  peristalsis 
is  sometimes  observed  on  opening  the  abdomen.  The  skin  is 
usually  flushed  and  hot,  and  is  covered  with  sweat  (hence  the 
need  of  protecting  the  patient  from  catching  cold) .  In  the  mouth 
and  throat  saliva  and  mucus  are  abundant.  The  pupils  are  in 
mid-dilatation  and  react  so  sluggishly  to  light  that  their  contrac- 
tion may  be  difficult  to  detect.  The  eye  reflexes  disappear,  the 
absence  of  the  corneal  or  conjunctival  reflex  being  one  of  the 
indications  that  the  patient  is  well  anesthetized.  The  heart  is 
regular  and  of  fair  force.  Its  rate  is  moderately  increased. 
Arterial  pressure  is  good,  but  in  prolonged  anesthesia  slowly 
falls.  The  respiration  is  regular  and  may  be  stertorous  or 
snoring,  or  may  be  impeded  by  the  tongue  or  the  collection  of 
saliva  and  mucus,  large  amounts  of  which  are  secreted  in  the 
throat  and  bronchi  (the  throat  must  be  kept  clean,  the  jaw  and 
tongue  kept  forward) .     The  temperature  falls,  so  that  the  patient 


280  PHARMACOLOGY  AND  THERAPEUTICS 

must  be  kept  well  covered.  All  sensation  and  nearly  all  the 
reflexes  are  abolished.  This  is  complete  surgical  anesthesia,  a 
state  in  which  the  patient  may  be  kept  for  a  considerable  length 
of  time.  The  anesthetist  recognizes  this  stage  when  the  corneal 
reflex  is  absent,  and  the  raised  arm  falls  limp,  i.  e.,  is  completely 
relaxed. 

If  the  patient  passes  beyond  this  stage,  he  goes  into  collapse, 
with  depression  of  the  vasoconstrictor  and  respiratory  cen- 
ters and  of  the  heart  muscle;  the  pupils  usually  become  dilated 
and  do  not  react  to  light. 

The  common  danger-signs  in  ether  anesthesia  are : 
i.  Increasing  weakness  or  increasing  rapidity  or  irregularity 
of  the  pulse.     It  should  be  remembered  that  the  heart  may  be 
quite  weak  before  its  rate  increases. 

2.  Slow,  shallow  respiration,  with  cyanosis. 

3.  Pupil  dilated  and  without  reaction  to  light. 

Recovery. — In  recovery  from  the  anesthesia  the  third  and 
second  stages  may  be  passed  through  slowly,  and  there  is  a 
tendency  for  the  patient  to  remain  asleep  until  awakened  by 
nausea  or  vomiting  or  some  other  disturbing  factor.  But  there 
may  be  a  period  of  struggling  and  incoherent  speech,  followed  by 
a  deep,  quiet  sleep;  or  a  period  of  prolonged  quiet  with  regular 
breathing  as  if  the  patient  is  deep  in  anesthesia,  and  then  sud- 
denly a  cry,  or  vomiting,  or  an  attempt  to  get  up.  A  careless  or 
inexperienced  anesthetist  may  allow  such  a  partial  recovery 
before  the  end  of  the  operation,  or  even  before  the  surgeon  begins 
work,  this  state  of  "false  anesthesia"  being  recognized  only 
when  the  patient  moves  or  gives  signs  that  he  is  going  to  vomit. 
It  is  a  standing  rule  that  if  the  pupil  reacts  readily  to  light,  more 
of  the  anesthetic  is  required. 

Vomiting  is  expected  when,  the  pulse  remaining  good,  there 
are  a  long  pause  in  the  breathing  and  a  paling  of  the  face.  The 
vomitus  consists  of  swallowed  mucus  and  saliva,  and  any  other 
material  that  may  be  in  the  stomach,  such  as  food.  As  muscular 
relaxation  prevents  its  full  expulsion,  the  head  should  be  turned  to 
one  side,  to  allow  the  vomitus  to  run  out  of  the  mouth;  otherwise 
the  vomitus  may  be  drawn  into  the  lungs. 

After-effects. — 1.  Usual — (a)  Vomiting  is  a  regular  sequel  of 
ether  anesthesia;  and  nausea  may  persist  for  two  or  three  days, 
with  disgust  for  food,  headache,  lassitude,  and  sometimes  a  per- 
sistent taste  of  ether.  The  vomiting  may  be  due  to  irritation  of 
the  stomach  by  the  ether  in  the  swallowed  secretions;  it  is  said 
to  be  absent  usually  in  rectal  anesthesia  or  intratracheal  insuffla- 
tion. The  taste  of  ether  is  due  to  suggestion,  or  to  the  slow  excre- 
tion of  the  last  portions  of  the  ether.     It  has  been  attributed  to  a 


ETHER   AND    CHLOROFORM   AS    GENERAL   ANESTHETICS       28l 

condition  of  acidosis.  If  it  persists  after  a  few  hours,  the  stomach 
may  be  lavaged  with  a  solution  of  sodium  bicarbonate;  or  30- 
grain  (2  gm.)  doses  of  sodium  bicarbonate  may  be  administered, 
or  1  ounce  (30  gm.)  of  glucose  (Beddard)  or  olive  oil  (Graham). 
Thirst  is  marked,  but  because  of  the  vomiting  tendency  cannot 
be  allayed.  Most  surgeons  allow  very  little  liquid  for  the  first 
few  hours,  e.  g.,  one  or  two  teaspoonfuls  of  water  each  hour  or 
half  hour.  The  thirst  is  less  if  the  patient  drinks  freely  of  water 
two  or  three  hours  before  the  operation. 

(b)  Distention  of  stomach  and  intestines  with  gas,  sometimes 
lessened  by  carminatives,  stupes,  enemata,  colon  irrigations,  the 
continuous  rectal  drop  method  of  Murphy,  or  by  physostigmine 
hypodermatically. 

(c)  Pain  in  the  back,  between  the  shoulders,  or  in  the  small 
of  the  back.     Lessened  by  change  of  posture,  special  pillows;  etc. 

2.  Untoward  Sequelae. — (a)  Of  the  respiratory  organs — bron- 
chitis, pneumonia,  edema  of  the  lungs,  or  the  lighting  up  of  a 
quiescent  tuberculous  process  in  the  lung.  The  danger  of  pneu- 
monia is  said  by  Mtiller  to  be  greatly  increased  if  ether  is  admin- 
istered a  second  time  within  a  few. days.  N.  G.  Davis  and  also 
Stursberg  have  brought  forward  some  evidence  that  in  some 
cases  the  post-ether  respiratory  troubles  may  be  due  to  the 
patients  catching  cold  rather  than  to  ether  irritation.  Stursberg, 
in  experimenting  with  dogs,  found  that  if  the  ether  were  allowed 
to  evaporate  freely  there  was  a  surface  chilling,  with  pronounced 
rise  in  arterial  pressure  from  reflex  contraction  of  the  internal 
arteries.  This  did  not  occur  from  chloroform.  With  the  open 
cone,  too,  the  ether  refrigeration  by  evaporation  at  the  mouth- 
piece makes  the  inhaled  vapor  very  cold,  and  this  in  itself  might 
be  enough  to  irritate  the  bronchi  and  lungs.  Hence  the  resort 
to  warmed  vapor  on  the  part  of  some  anesthetists,  the  container 
being  placed  in  warm  water.  There  is  evidence,  both  pro  and 
con,  as  to  the  value  of  warming  the  vapor.  Seelig  (191 1)  found 
that  the  gas  inhaled  caused  no  cooling  in  the  trachea,  but  that 
the  evaporating  vapor  cooled  the  air  about  the  patient. 

(b)  Of  the  kidneys — albuminuria  and  sometimes  acute  ne* 
phritis. 

(c)  Post-operative  Gastric  or  Intestinal  Paralysis. — Treated  by 
strychnine  and  lavage,  intestinal  irrigations,  enemata,  or  eserine, 
to  grain  (0.0015  gm.). 

(d)  Local  injuries,  as  conjunctivitis,  from  ether  getting  into  the 
eye,  or  from  injury  done  by  the  linger  of  the  anesthetist  in  testing 
the  corneal  reflex ;  and  a  sore  tongue  from  the  use  of  tongue  forceps, 
or  from  the  passing  of  a  suture  through  the  tongue  to  hold  it 
forward. 


202  PHARMACOLOGY  AND    THERAPEUTICS 

Helpful  or  Preventive   Measures   in  Ether  Anesthesia. — 

I.  Preliminary  Anesthetization  with  Nitrous  Oxide  or  Ethyl 
Chloride. — This  practically  does  away  with  the  irritation, 
struggling,  and  intoxication  of  the  first  and  second  stages.  The 
ether  is  begun  when  the  patient  is  in  the  third  stage.  There 
may  be  a  long  movement  of  cessation  of  breathing  as  the 
change  is  made,  but  regular  breathing  is  soon  resumed. 

2.  Preliminary  Anesthetization  with  Chloroform. — This  short- 
ens the  first  and  second  stages.  In  athletes,  alcoholics,  or  the 
obese  it  is  easier  to  bring  on  the  anesthesia  with  chloroform, 
ether  being  substituted  as  soon  as  the  patient  is  well  anesthetized. 

3.  Preliminary  Administration  of  Sedative  Drugs. — About 
half  an  hour  before  the  operation  morphine  sulphate,  yi  grain 
(0.015  gm-)>  or  morphine  sulphate,  Y^  grain  (0.01  gm.),  with 
scopolamine  hydrobromide,  y-jj-o  grain  (0.0006  gm.),  or  chlore- 
tone,  15  grains  (1  gm.)  by  mouth.  These  quiet  the  patient's 
mind  and  lessen  fear,  anxiety,  and  other  psychic  disturbances. 
They  also  expedite  the  anesthetization  and  make  less  of  the 
anesthetic  necessary.  Crile  has  shown  that  shock  is  less  if  the 
patient's  mind  is  at  ease.  The  morphine  is  a  powerful  depres- 
sant of  the  respiratory  center,  and  may  cause  contraction  of  the 
pupil. 

4.  Injection  of  atropine  sulphate — y^  grain  (0.0006  gm.) 
or  j-q  grain  (0.0012  gm.),  to  stimulate  the  respiratory  center, 
to  lessen  the  secretions  of  saliva  and  mucus,  and  to  prevent 
primary  vagus  stimulation.  It  may  interfere  with  the  usual 
pupil  reactions. 

5.  Warming  the  Vapor  and  Diluting  with  Oxygen  Instead  of 
Air. — Gwathmey  gives  data  of  experiments  on  cats  which  indi- 
cate that  either  of  these  procedures  lessens  the  toxicity  of  both 
ether  and  chloroform.  He  warms  the  ether  with  a  thermolite 
bottle  or  by  setting  the  container  in  hot  water.  This  at  least 
tends  to  counteract  the  great  coldness  about  the  mouth  caused 
by  the  evaporation  of  more  or  less  of  the  vapor. 

6.  Having  the  Stomach  Empty. — To  avoid  the  danger  of  vomit- 
ing food  and  having  it  drawn  into  the  lungs.  This  is  accomp- 
lished ordinarily  by  abstention  from  food  for  several  hours,  but 
in  an  emergency  by  lavage. 

7.  Reassuring  the  Patient. — Crile  states  that  psychic  distur- 
bances, fear,  anxiet)',  etc.,  distinctly  increase  the  chance  of  col- 
lapse; and  in  very  nervous  cases,  especially  those  with  hyper- 
thyroidism, he  takes  time — even  days — to  get  the  patient  into 
a  calm  mental  state. 

8.  Feeding  with  carbohydrates  and  water — just  long  enough 
before  the  operation  to  allow  the  stomach  to  empty  itself.     This 


CHLOROFORM   ANESTHESIA  283 

has  been  shown  to  prevent  fatty  degeneration  of  the  liver  and 
to  lessen  post-operative  nausea.  It  has  been  shown  that  the 
dangers  of  ether  are  greater  in  starvation  and  fatigue,  so  it  is 
considered  wise  not  to  leave  the  patient  without  food  and  rest 
for  too  long  a  period  before  the  operation. 

9.  Administering  sodium  bicarbonate,  }4  ounce  (15  gm.)  in 
solution  by  rectum  half  an  hour  before  the  anesthetic. 

INDICATIONS  FOR  ETHER  AS  ANESTHETIC 
Ether,  especially  with  proper  preventive  precautions,  is 
preferred  to  chloroform  in  almost  all  cases,  including  those  with 
heart  or  kidney  disease.  It  is  not  employed  in  cases  with  severe 
bronchial  or  pulmonary  inflammation,  or  in  very  old  age,  where 
the  ether  intoxication  might  result  in  rupture  of  a  sclerosed 
vessel  or  in  some  other  injury.  In  brain  surgery  Horsley  prefers 
chloroform  because  of  the  danger  of  a  rise  in  general  arterial 
pressure  from  ether  and  the  resultant  extensive  oozing  of  blood; 
while  Crile  uses  ether  because  of  the  special  danger,  in  such  sur- 
gery, of  depression  of  the  medullary  centers. 

When  ether  fails  to  bring  about  muscular  relaxation,  as  in 
some  alcoholics  or  very  robust  athletic  persons;  or  when  the 
secretions  of  the  throat  are  so  abundant  as  to  become  dangerous, 
chloroform  alone,  or  chloroform  followed  by  ether,  may  be 
employed.  It  is  reported  that  in  hot  countries  and  at  high  alti- 
tudes anesthesia  with  ether  is  difficult  to  obtain;  but  Squire 
(Lancet,  1913)  reports  the  satisfactory  use  of  ether,  even  with 
the  temperature  1 20°  F.  in  the  shade. 

Where  a  very  quick  and  very  transitory  effect  is  desired,  as 
in  obstetrics,  chloroform  is  usually  preferred.  But  a  number  of 
cases  of  fetal  death  from  chloroform  are  reported;  and  in 
some  cases,  though  the  child  is  born  alive,  it  never  breathes 
because  of  the  depression  of  the  respiratory  center. 

CHLOROFORM  ANESTHESIA 
In  the  production  of  anesthesia  by  chloroform  there  are  four 
stages,  as  in  ether  anesthesia,  and  the  symptoms  are  the  same  in 
nature.  But  chloroform,  properly  diluted  with  air,  is  not  un- 
pleasant to  the  patient,  is  scarcely  irritating  to  nose  and  throat, 
and  is  more  prompt  in  producing  anesthesia,  hence  the  first  and 
second  stages  are  comparatively  short  and  not  so  disagreeable, 
and  the  stage  of  intoxication  is  seldom  troublesome.  With 
chloroform  a  patient  may  be  anesthetized  in  from  two  to  five 
minutes;  with  ether  it  may  take  ten  or  fifteen  minutes.  The 
recovery  is  correspondingly  rapid.  Again,  the  amount  of  ether 
required  is  much  greater,  it  being  reckoned  in  ounces,  while  that 


284  PHARMACOLOGY  AND   THERAPEUTICS 

of  chloroform  is  reckoned  in  drams.  In  chloroform  anesthesia 
the  face  is  usually  pale  rather  than  flushed,  and  the  breathing  is 
quiet;  in  fact,  so  different  is  this  from  the  ether  effect,  that  it 
sometimes  worries  the  anesthetist  or  surgeon  who  has  been 
regularly  employing  ether. 

Chloroform  would  therefore  have  some  decided  advantages 
over  ether  were  it  not  for  the  fact  that  it  is  less  safe.  The  ad- 
vantages are:  (1)  Smaller  dose.  (2)  Simplicity  of  administra- 
tion— a  small  container  and  small  mask,  a  good  thing  in  field 
work;  or  a  few  drops  on  a  handkerchief.  (3)  Easier  and  pleas- 
anter  for  patient.  (4)  Less  marked  stage  of  intoxication.  (5) 
Anesthesia  more  quickly  produced.  (6)  Anesthesia  more  quickly 
recovered  from.  (7)  No  bronchial  or  lung  irritation.  (8) 
Respiratory  mucus  and  saliva  not  excessive.  (9)  Nausea  and 
vomiting  less  common  after-effects.  (10)  Chloroform  is  not 
inflammable,  and  its  vapor  does  not  make  an  explosive  mixture 
with  air. 

These  are  decided  advantages  in  the  administration  of  an 
anesthetic,  yet  in  spite  of  them  ether  is  preferred  because 
chloroform  is  more  dangerous. 

The  special  dangers  of  chloroform  anesthesia  are — (1)  Early 
heart  failure;  (2)  the  cardiac  depression  with  limited  margin  of 
safety;  (3)  delayed  chloroform  poisoning. 

The  First  Danger. — This  comes  from  too  concentrated  vapor 
at  the  start.  In  the  laboratory  it  is  not  uncommon  that  when  a 
dog  is  made  to  inhale  concentrated  chloroform  its  heart  will  be 
promptly  slowed,  and  in  some  cases  will  stop  and  not  beat  again. 
Death  from  concentrated  vapor  takes  place  before  enough  chloro- 
form has  been  absorbed  to  cause  death  by  systemic  action.  But 
if,  before  the  inhalation,  a  dog  is  given  a  hypodermatic  of  a  large 
dose  of  atropine,  or  if  his  vagus  nerves  are  cut,  even  very  con- 
centrated chloroform  does  not  cause  a  stoppage  of  the  heart  at 
all.  The  cessation  of  the  heart-beat  must,  therefore,  be  due  to 
excessive  vagus  activity.  But  this  stoppage  of  the  heart  is  also 
prevented  if  the  laryngeal  nerves  are  cut  or  if  the  throat  is 
anesthetized  with  cocaine;  therefore  the  effect  is  a  reflex  one,  and 
the  stimulation  of  the  vagus  is  the  result  of  the  irritant  action  of 
the  chloroform  upon  the  throat. 

It  has  been  surmised  that  many  of  the  chloroform  casualties 
have  taken  place  in  this  way,  for  they  have  occurred  in  the  first 
few  moments  of  the  administration,  before  the  surgeon  had  begun 
to  operate  and  before  the  stage  of  full  anesthesia  had  been  reached 
(90  per  cent,  of  casualties  take  place  in  the  first  fifteen  minutes — 
Gwathmey).  This  possibility  of  excessive  reflex  inhibition, 
therefore,  becomes  a  serious  matter. 


CHLOROFORM    ANESTHESIA  285 

Ordinarily,  it  is  impossible  to  kill  an  animal  by  excessive  vagus 
stimulation,  for  after  a  brief  period  the  heart  will  go  on  beating 
again  in  spite  of  the  vagus.  But  in  the  administration  of  a  gas 
by  the  lungs  the  area  of  absorption  is  large;  and  the  pulmonary 
blood,  charged  heavily  with  vapor,  passes  instantly  to  the  left 
heart  and  poisons  its  muscles. 

Cases  are  not  reported  of  excessive  vagus  inhibition  from  the 
use  of  ether  as  an  anesthetic,  but  Muehlberg  and  Kramer  have 
shown  that  an  injection  into  the  carotid  artery  of  as  little  as  2 
minims  of  ether  or  chloroform  can  cause  almost  instant  death 
in  a  rabbit.  They  also  show  that  even  if  vagus  inhibition  is 
prevented  the  heart  is  weakened.  The  conclusion  is  that  when 
death  takes  place  during  the  early  stages  of  chloroform  adminis- 
tration there  are  probably  three  conditions  present,  viz.:  (1) 
Weakening  of  the  heart  due  to  direct  action  of  the  poison.  This, 
absorbed  by  the  extensive  lung  surface,  makes  a  concentrated 
solution  in  the  pulmonary  blood  which  passes  at  once  into  the 
left  heart  and  to  the  coronaries;  (2)  reflex  vagus  stimulation 
and  (3)  reflex  vasoconstrictor  stimulation.  The  combination 
of  these  three  effects,  viz.,  inhibition,  muscle  poisoning,  and  in- 
creased peripheral  resistance,  results  in  heart  failure. 

If  the  chloroform  is  given  to  a  dog  in  sufficient  dilution  with 
air  to  avoid  the  local  irritation  of  the  throat,  both  the  vagus 
center  and  the  throat  soon  become  less  sensitive,  and  then  it  is 
impossible  to  produce  this  vagus  inhibition  with  any  strength  of 
chloroform.  Hence  the  excessive  reflex  activity  of  the  vagus 
may  be  prevented  by  avoiding  too  great  concentration  of  the 
vapor  at  the  outset,  or  by  a  preliminary  injection  of  a  large  dose 
of  atropine,  or  by  thorough  cocainization  of  the  pharynx  and 
larynx.  (See  experiments  of  Levy  and  Lewis  under  Pharmaco- 
logic Action  above.) 

The  Second  Danger. — We  have  already  learned  that  chloro- 
form is  much  more  depressing  to  the  muscles  of  the  heart  and 
arteries  and  to  the  medullary  centers  than  is  ether.  This  de- 
pressing effect  is  seen  almost  from  the  start,  while  with  ether  such 
a  depression  is  not  noted  except  in  prolonged  anesthesia  or  from 
overwhelming  doses  of  concentrated  vapor.  In  addition  the 
chloroform  has  a  special  affinity  for  the  heart  muscle,  so  that  it 
is  less  readily  discharged  from  it  than  ether.  Hence  resuscita- 
tion is  difficult. 

These  factors  make  the  margin  of  safety  for  chloroform  a 
narrow  one,  the  stage  of  complete  anesthesia  being  much  nearer 
the  stage  of  collapse  than  with  ether.  Furthermore,  when  col- 
lapse comes  on  from  ether,  the  patient  may  often  be  restored 


286  PHARMACOLOGY  AND   THERAPEUTICS 

with  comparative  ease,  while  when  the  signs  of  collapse  appear 
from  chloroform  the  chances  of  recovery  are  small. 

The  Third  Danger. — In  the  last  few  years  a  great  many  cases 
have  been  reported  in  which  the  patient,  after  apparently  recover- 
ing from  chloroform,  would  pass  in  a  few  hours  or  days  into 
a  condition  of  marked  prostration,  delirium,  coma,  and  death. 
This  condition  has  become  known  as  delayed  chloroform  poisoning, 
and  it  has  been  the  subject  of  much  careful  study. 

The  symptoms  appear  in  from  ten  hours  to  six  days  after  the 
anesthetization.  The  onset  may  be  gradual  or  sudden.  In  the 
former  the  patient  does  not  fully  recover  after  the  anesthesia, 
and  gradually  passes  into  a  state  of  prostration  with  delirium, 
coma,  and  death.  When  the  onset  is  sudden,  the  patient  re- 
covers from  the  anesthesia  and  is  apparently  doing  well,  and  the 
first  indications  of  anything  wrong  are  marked  cerebral  disturb- 
ance, with  the  sudden  appearance  of  periods  of  wild  delirium, 
with  shrieking  and  struggling,  alternating  with  periods  of  stupor 
or  coma.  There  may  be  vomiting  of  blood,  cyanosis,  jaundice, 
intestinal  or  renal  hemorrhage,  and  sweetish,  acetone  breath. 
The  urine  may  contain  albumin,  casts,  and  blood,  and  in  addi- 
tion a  high  ammonia  nitrogen  and  low  urea  nitrogen,  and  in 
some  cases  acetone,  diacetic  acid,  and  beta-oxybutyric  acid. 
The  delirium  and  coma  are  followed  by  collapse,  death  taking 
place  twelve  to  sixty  hours  after  the  first  appearance  of  the 
symptoms. 

Postmortem  examination  regularly  reveals  extensive  fatty 
degeneration  of  the  liver,  with  necrotic  areas  in  the  lobules  and 
scattered  hemorrhages,  frequently  some  fatty  degeneration  in 
the  kidney  tubules  with  hemorrhagic  areas,  and  sometimes  fatty 
degeneration  in  the  heart  and  arteries.  Degeneration  in  the 
cardiac  ganglia  has  also  been  reported.  There  may  be  hemor- 
rhages in  the  stomach  and  intestines  and  in  the  serous  membranes. 

In  experiments  on  dogs  it  has  been  found  that  in  some  in- 
stances even  fifteen  minutes'  mild  anesthetization  from  chloro- 
form has  been  enough  to  produce  areas  of  fatty  degeneration  in 
the  liver.  And  it  is  believed  that  fatty  degeneration  of  the  liver 
of  some  degree  must  take  place  in  every  full  chloroform  anes- 
thesia, though  ordinarily  this  is  rapidly  recovered  from. 

Miiller  (1905)  and  Offergeld  in  the  same  year  demonstrated 
that  in  animals  anesthetized  twice  within  a  few  days  the  changes 
were  more  pronounced,  and  delayed  chloroform  poisoning  more 
likely  to  follow.  It  has  also  been  shown  experimentally  that  a 
preliminary  impairment  of  the  kidneys  or  much  hemorrhage 
favors  the  liver  destruction.  In  humans,  delayed  chloroform 
poisoning   has   occurred  most   commonly  in   children.     It  has 


CHLOROFORM   ANESTHESIA  287 

rarely  been  recovered  from.  A.  Weir  reports  one  case  of  recovery 
following  the  administration  of  15  gm.  of  glucose  in  500  c.c.  of 
water  by  stomach  (tube  through  nares)  every  four  hours,  and 
10  gm.  of  glucose  in  100  c.c.  of  water  by  rectum. 

The  conditions  which  favor  the  development  of  delayed 
chloroform  poisoning  are  believed  to  be:  Liver  abscess,  kidney 
disease,  anemia,  especially  that  due  to  hemorrhage,  alcoholism, 
obesity,  the  lymphatic  diathesis,  childhood,  previous  chloroform 
anesthesia  within  two  or  three  days,  and  prolonged  anesthesia. 

Several  observers  have  reported  acute  liver  atrophy  following 
chloroform. 

To  repeat,  then,  the  three  dangers  in  chloroform  anesthesia, 
which  are  slight  or  absent  in  ether  anesthesia,  are  the  following'. 

1.  Sudden  death  before  complete  anesthesia  is  induced. 

2.  Small  Margin  of  Safety. — The  depression  of  heart  and 
arteries  and  of  the  vasoconstrictor  and  respiratory  center,  makes 
a  small  margin  of  safety  between  the  stages  of  anesthesia  and 
collapse,  and  difficulty  in  restoring  the  patient  after  signs  of 
danger  are  manifest.  This  is  especially  true  in  persons  with  the 
lymphatic  diathesis. 

3.  Delayed  chloroform  poisoning. 

It  is  on  account  of  these  that  the  use  of  chloroform  has  been 
quite  generally  abandoned  as  a  general  anesthetic,  except  in  a 
few  special  types  of  cases. 

Possible  preventive  measures  are: 

1.  To  prevent  vagus  stoppage  of  heart — atropine,  -gV  grain 
(0.00 1  gm.)  by  hypodermatic,  cocaine  to  throat,  or  well-diluted 
chloroform  at  the  start. 

2.  To  retard  cardiac  and  central  depression — oxygen,  avoid- 
ance of  too  long  a  period  of  starvation  before  the  operation,  and 
the  use  of  a  minimum  quantity  of  the  anesthetic. 

3.  To  lessen  or  check  the  fatty  degenerations — oxygen  and 
glycogen-forming  food  (glucose,  sugar,  etc.),  with  avoidance  of 
too  long  a  period  of  starvation  before  the  anesthesia.  Hunter 
recommends  that  the  patient  be  given  a  nutritious  and  easily 
digestible  meal,  well  sweetened,  two  or  three  hours  before  the 
anesthetic. 

Contraindications  to  Chloroform.— Diabetes,  sepsis,  hem- 
orrhage, eclampsia,  conditions  of  much  enfeeblement,  fatty 
degeneration,  and  the  lymphatic  diathesis. 

Acidosis  in  General  Anesthesia. — The  development  of 
acidosis  following  anesthesia,  as  shown  by  the  appearance  of 
acetone,  diacetic  acid,  and  beta-oxybutyric  acid  in  the  urine,  is  a 
matter  of  considerable  importance. 

According  to  Ewing,  Becker  found  acetonuria  in  two-thirds 


255  PHARMACOLOGY  AND  THERAPEUTICS 

of  all  anesthetized  patients,  the  condition  being  most  pronounced 
in  children,  and  more  marked  in  women  than  in  men.  It  ap- 
peared in  the  first  or  second  portion  of  urine  passed,  and  per- 
sisted eight  or  nine  days.  Abram  found  acetone  in  25  cases,  and 
more  frequently  after  chloroform  than  after  ether.  Wallace  and 
Gillespie  found  it  in  25  per  cent,  of  cases  before  operation  and  in 
about  60  per  cent,  after  operation.  Waldvogel  observed  it  in 
75  per  cent,  of  50  cases,  and  in  13  of  them  noted  diacetic  and 
beta-oxybutyric  acid. 

These  observations  indicate  the  marked  danger  of  general 
anesthesia  in  all  conditions  associated  with  acidosis,  such  as 
diabetes  and  the  various  toxemias,  especially  those  associated 
with  liver  degeneration.  Therefore  general  anesthesia,  whether 
from  chloroform  or  ether,  requires  special  consideration  in  dia- 
betes, eclampsia,  vomiting  of  pregnancy,  cyclic  vomiting,  acute 
yellow  atrophy  of  the  liver,  general  sepsis,  uremia,  and  in  those 
cases  of  intestinal  obstruction  with  marked  auto-intoxication. 
In  all  these  types  of  cases  the  dangers  of  chloroform  are  greater 
than  those  of  ether. 

Of  acetonuria,  Wallace  and  Gillespie  say  that  the  vomiting 
after  twelve  hours  is  regularly  related  to  the  amount  of  acetone, 
and  this  can  be  lessened  by  lavage  with  sodium  bicarbonate. 
But  for  administration  as  a  prophylactic  before  the  anesthesia 
glucose  is  to  be  preferred  to  sodium  bicarbonate. 

Effect  on  Injections  and  Immunity. — Graham-Rubin  (1907) 
showed  that  hypodermatics  of  alcohol,  ether,  or  chloroform 
rendered  rabbits  more  susceptible  to  systemic  infection  with 
streptococcus  and  pneumococcus;  and  Stewart  (1907)  showed 
that  this  was  especially  true  of  infections  to  which  immunity  was 
chiefly  phagocytic.  In  other  immunity  studies  also  it  has  been 
shown  of  alcohol,  which  is  of  the  same  class,  that  after  the  injec- 
tion of  an  antigen  it  retards  the  formation  of  the  antibodies. 
The  same  is  probably  true  of  ether  and  chloroform. 

Francois  (1910)  found  that  the  phagocytic  activity  of  the 
leukocytes  was  lessened  or  abolished  after  chloroform  or  ether 
anesthesia,  and  that  this  effect  lasted  for  twenty-four  hours. 

Graham  (1910)  also  found  that  the  phagocytic  power  was 
not  restored  for  many  hours.  He  observed  that  while  saline 
infusion  did  not  hasten  the  restoration,  olive  oil  by  rectum,  or 
lecithin  (0.1  gm.)  subcutaneously,  shortened  the  period  of  phago- 
cytic depression. 

ADMINISTRATION  OF   ANESTHETICS 
Ether  for  general  anesthesia  is  administered  by  inhalation, 
by  intratracheal  insufflation,  by  rectum,  or  intravenously. 


ADMINISTRATION    OF   ANESTHETICS  289 

The  inhalation  methods  are : 

1.  The  Open  Cone  Method. — Usually  an  extemporized  cone 
made  of  a  towel  and  some  paper,  with  a  handful  of  absorbent 
cotton  or  gauze  inside  to  receive  the  ether.  It  may  be  made 
with  a  special  frame,  as  the  Allis  Inhaler.  The  open  cone  allows 
much  air  to  be  drawn  in,  so  to  get  the  concentration  of  ether 
required  to  produce  anesthesia  it  is  necessary  to  place  a  large 
quantity  of  ether  in  the  cone  and  to  exclude  the  air  as  much  as 
possible  by  wet  towels.  In  fact,  to  hasten  the  process  the  anes- 
thetist is  sometimes  tempted  to  exclude  too  much  air,  with  re- 
sulting cyanosis. 

At  the  commencement,  the  cone,  containing  ^  to  i  ounce 
of  ether,  is  held  several  inches  from  the  face,  but  as  the  patient 
becomes  accustomed  to  the  vapor  is  gradually  brought  nearer. 
In  two  or  three  minutes,  when  the  local  anesthesia  has  come  on, 
it  is  placed  down  over  nose  and  mouth,  fitting  closely  to  the  face. 
If  the  patient  stops  breathing,  owing  to  the  irritation  of  the 
ether,  the  mask  may  be  removed  for  a  moment,  then  replaced  as 
soon  as  he  takes  a  breath  of  air.  Sometimes  a  change  from  shal- 
low to  deep  breathing  will  send  the  patient  under  very  quickly, 
as  a  large  amount  of  ether  is  at  once  drawn  into  the  lungs. 

2.  The  Drop  Method. — Ether  is  rapidly  dropped,  about  150 
drops  to  the  minute,  upon  a  large  Esmarch  chloroform  mask 
covered  with  flannelette.  This  is  placed  close  over  nose  and 
mouth,  and  may  be  wrapped  around  with  a  wet  towel,  so  that  it 
fits  closely  to  the  face.  This  method  allows  free  air-supply  and 
reduces  the  danger  of  cyanosis  to  the  minimum.  Ladd  and 
Osgood,  and  also  Williams  and  Young,  claim  that  by  this  method 
acetonuria  is  less  frequent  than  with  the  cone. 

3.  The  closed  inhalers,  Bennett's,  Clover's,  Hewitt's,  etc.,  are 
employed  with  the  double  purpose  of  preventing  waste  of  ether 
and  of  regulating  the  relative  supply  of  ether  and  air.  With 
these  a  bagful  (one  or  more  gallons)  of  nitrous  oxide  gas  is  gener- 
ally administered  first,  to  shorten  the  first  and  second  stages, 
then  the  ether  connection  is  attached,  and  the  supply  of  ether 
and  air  regulated  by  valves.     There  is  little  waste  of  ether. 

Chloroform  is  administered  by  inhalation  or  intravenously. 
For  inhalation  it  may  be  administered  by  the  drop  method  on  an 
open  mask  or  by  a  closed  inhaler. 

1 .  In  the  drop  method,  from  60  to  600  drops  (4  drops  =  1 
minim)  are  required  to  produce  anesthesia,  and  about  20  to  40 
drops  per  minute  to  maintain  it.  A  small  wire  frame  covered 
with  flannelette  or  several  thicknesses  of  line  gauze  is  used  as  the 
mask.  At  the  start  the  mask  is  held  a  few  inches  from  the  face, 
and  is  gradually  brought  nearer  until  it  is  close  to  the  nose  and 
19 


290  PHARMACOLOGY   AND   THERAPEUTICS 

mouth,  though  it  does  not  lit  closely  over  the  face  like  an  ether 
mask.  As  CHC13  burns  the  skin,  the  nose,  mouth,  and  chin 
should  always  be  protected  by  a  little  vaseline. 

2.  The  closed  inhalers  are  of  the  types  of  Harcourt  or  Gwath- 
mey,  either  of  which  is  arranged  to  allow  a  chloroform  strength 
of  0.1  to  2  per  cent.  As  it  frequently  takes  a  4  per  cent,  vapor 
to  produce  anesthesia,  Gwathmey's  contains  an  opening  covered 
with  flannelette,  which  permits  additional  CHC13  to  be  given  as 
desired.  A  method  of  self-administration  is  sometimes  used  in 
labor,  the  patient  holding  above  the  face  the  ordinary  chloroform 
mask  or  a  tumbler  containing  blotting-paper  wet  with  chloro- 
form. As  the  anesthetic  takes  effect  and  consciousness  is  abol- 
ished, the  arm  drops  and  lets  the  mask  or  tumbler  fall  away 
from  the  face.  The  anesthesia  is  thus  just  enough  to  lessen  the 
uterine  contractions  and  render  the  patient  lightly  insensible. 

Some  General  Remarks  about  Administration. — Before  the 
administration  anything  loose  in  the  mouth,  such  as  false  teeth, 
should  be  removed.  The  patient  should  be  reassured  and 
gotten  into  a  good  frame  of  mind,  for  the  psychic  factor  is  im- 
portant. Then  he  is  told  to  close  the  eyes  and  to  breathe  calmly 
and  normally;  or  he  may  be  told  to  count  1,  2,  3,  4,  etc.,  so  that 
his  mind  will  be  occupied.  Gwathmey  sometimes,  especially 
with  children,  places  a  few  drops  of  cologne  on  the  mask  at  the 
start,  to  give  the  patient  confidence,  then  gradually  adds  the 
chloroform  or  ether.  He  has  recently  discovered  that  when  the 
ether  vapor  is  passed  through  the  volatile  oil  of  orange  placed 
in  a  bottle  with  hot  water,  the  odor  of  ether  is  completely  dis- 
guised, and  the  patient  takes  it  without  struggling  or  resistance. 

The  quantity  of  ether  required  to  produce  anesthesia  by  an 
open  inhaler  is  about  5  to  10  ounces,  depending  on  who  gives  it 
and  who  takes  it,  with  a  concentration  of  4  to  6  per  cent,  or  in 
some  cases  even  10  per  cent.  The  quantity  required  to  main- 
tain anesthesia  is  about  4  to  8  ounces  an  hour,  with  concentra- 
tion of  3  to  4  per  cent.  With  the  closed  inhalers,  which  are  less 
wasteful,  only  one-third  to  one-half  as  much  ether  is  employed. 

The  amount  of  chloroform  required  to  produce  anesthesia  is 
about K  dram  (2  c.c.)  per  minute  for  from  two  to  five  minutes,  at  a 
concentration  of  2  to  4  per  cent.,  while  to  maintain  anesthesia  it 
takes  about  6  to  1 2  drams  an  hour  at  a  concentration  of  1  to  2  per 
cent.  To  continue  the  anesthesia  for  any  length  of  time  with  the 
vapor  "at  a  concentration  of  over  2  per  cent,  is  dangerous. 

Skill  in  administering  a  general  anesthetic  involves  not  merely 
the  prevention  of  death,  but  also  the  leaving  of  the  patient  in 
the  best  possible  physical  and  mental  condition  after  the  opera- 
tion.    With  both  chloroform  and  ether  the  danger  lies  in  over- 


RECTAL    OR    COLONIC    ANESTHESIA  29 1 

concentration  of  the  vapor  or  surcharging  of  the  blood  by  too  rapid 
administration,  rather  than  in  the  total  quantity  of  the  drug 
employed  in  any  given  anesthesia. 

It  is  wise  to  avoid  anesthetizing  beyond  the  point  necessary, 
for  if  the  patient  becomes  too  deeply  anesthetized,  and  then,  by 
stoppage  of  the  administration,  is  allowed  to  come  back  to  the 
condition  of  surgical  anesthesia,  his  centers  are  more  depressed, 
and  he  is  in  a  weaker  and  less  resistant  state  than  if  he  has  been 
kept  steadily  at  the  proper  degree  of  anesthesia  throughout. 
To  administer  rapidly  a  large  quantity  of  concentrated  vapor, 
i.  e.,  to  "push"  the  ether  or  chloroform  when  the  patient  unex- 
pectedly shows  signs  of  recovery,  adds  to  the  depression  of  the 
respiratory  and  vasoconstrictor  centers;  and  it  is  unjustifiable  to 
try  and  cover  up  the  faults  of  carelessness  or  inexperience  by 
such  a  method.  It  is  better  to  proceed  carefully,  even  though 
the  surgeon  is  kept  waiting. 

It  has  recently  been  suggested  that  the  limbs  might  be  ex- 
cluded by  tight  bandaging  or  by  tight  elastic  bands  at  their 
proximal  ends.  This  renders  necessary  only  about  half  as  much 
of  the  anesthetic,  and  makes  recovery  more  prompt  on  removing 
the  bands.  It  is  stated  that  limbs  may  be  kept  thus  without 
circulation  for  half  an  hour  with  impunity.  Delageniere  (Arch. 
Prov.  de  Chir.,  August,  191 1)  used  this  method  1144  times  with 
chloroform  and  35 1  times  with  ether.  The  chief  unpleasant 
effects  are  tingling  of  the  limbs  for  several  hours,  minute  ecchy- 
moses  of  the  skin,  possibly  paralysis  or  phlebitis.  The  last- 
named  writer  had  4  cases  of  phlebitis  of  the  lower  limbs. 

RECTAL  OR  COLONIC  ANESTHESIA 
Ether  is  sometimes  given  by  rectum,  the  bowel  being  cleansed 
beforehand  with  an  enema  of  salt  solution  or  solution  of  sodium 
bicarbonate.  The  properly  diluted  vapor  is  administered  by  a 
special  apparatus.  Free  exit  of  vapor,  and  oxygen  as  the  diluent, 
are  considered  absolute  necessities  by  some  rectal  anesthetists. 
The  author  has  learned  of  a  case  of  colonic  anesthesia  in  which 
enormous  distention  and  rupture  of  the  colon  occurred.  This 
was  presumably  due  to  the  combination  of  three  factors,  viz., 
the  expansion  of  the  ether  vapor  by  the  warmth  of  the  body,  the 
non-resistance  of  the  bowel,  owing  to  its  loss  of  muscular  tone 
and  the  lack  of  a  free  exit  for  the  gas.  Rectal  anesthesia  is  a 
means  of  avoiding  the  distress  of  the  first  stage  and  the  irritation 
of  the  respiratory  tract;  it  is  said  to  lessen  the  post-ether  nausea 
and  vomiting.  It  is  sometimes  followed  by  hemorrhage  from 
the  bowel  or  by  diarrhea  or  colitis  from  irritation  of  the  bowel, 
so  must  be  used  with  great  care,  and  it  is  not  a  method  for  general 


292  PHARMACOLOGY  AND  THERAPEUTICS 

use.  Cunningham  reports  death  from  it  in  a  case  of  amebic 
colitis. 

Its  special  value  is  in  operations  about  the  head  and  neck, 
or  in  patients  with  inflammatory  conditions  of  the  respiratory 
tract. 

Arnd  has  used  a  5  per  cent,  solution  of  ether  in  saline  by 
rectum;  after  scopolamine-morphine  or  pantopon,  a  liter  of  the 
ether  solution  brought  on  unconsciousness  almost  immediately. 

INTRAVENOUS  GENERAL  ANESTHESIA 

After  experiments  with  cats  and  dogs  Burkhardt  (1909)  tried 
intravenous  chloroform  in  four  human  patients.  One  case 
developed  hemoglobinuria.  Giani  used  an  intravenous  infusion 
of  saline  saturated  with  chloroform  (100  c.c.  =  0.6  gm.  CHC13), 
introducing  55  c.c.  the  first  minute  in  the  saphenous  vein,  and 
1 100  c.c.  altogether,  representing  6.6  gm.  CHC13.  The  anes- 
thesia lasted  forty  minutes.  Seven  minutes  after  the  cessation 
of  the  infusion  the  patient  roused  up.  Muscular  relaxation  was 
present  early  and  there  was  no  post-operative  vomiting.  Later, 
Burkhardt  (191 1)  employed  ether  in  250  cases,  using  a  5  per  cent, 
solution  in  normal  saline  at  82. 40  F.  (280  C).  He  found  that 
it  required  about  80  c.c.  per  minute  and  a  total  of  500  c.c.  to 
abolish  the  reflexes  in  a  man.  There  was  no  vomiting,  no  cyano- 
sis, no  respiratory  disturbance.  Kiittner  used  it  in  23  cases  and 
thought  it  dangerous.  In  one  case  the  blood  clotted,  and  in  two 
there  was  "pulmonary  infiltration "  on  the  following  day.  Hage- 
mann  uses  the  mixture  at  a  temperature  of  100.40  F.  (380  C), 
at  which  temperature  only  4.68  per  cent,  dissolves. 

Dodge,  of  Boston  (1911),  recommends  it  in  operations  about 
the  head  and  neck,  in  hemorrhage,  in  weak  cachectic  patients, 
and  in  diseases  of  the  respiratory  tract. 

It  has  been  reported  to  me  by  Gwathmey  that  by  this  method 
anesthesia  is  very  easily  regulated. 

ANESTHESIA  BY  INTRATRACHEAL  INSUFFLATION 
In  1909  Meltzer  and  Auer,  working  with  dogs,  found  that 
the  ventilation  of  the  alveolar  air  can  be  accomplished,  and  that 
an  animal  can  be  kept  alive  and  in  good  condition  by  a  stream  of 
air  blown  through  a  tube  passed  down  the  trachea  nearly  to  the 
bifurcation.  Even  after  curare  to  suspend  all  action  of  the 
striated  respiratory  muscles  the  animal  could  be  kept  alive  for 
hours.  In  fact,  they  had  discovered  a  wonderful  method  of 
performing  artificial  respiration. 

Then  they  found  that,  by  passing  the  stream  of  air  over 
ether,  they  could  anesthetize  the  animal,  and  at  the  same  time 


TREATMENT  OF  UNTOWARD  SYMPTOMS         293 

keep  up  a  sufficient  degree  of  positive  intrathoracic  pressure  to 
prevent  collapse  of  the  lungs  in  intrathoracic  surgery.  This 
method  has  now  become  extensively  employed  for  anesthesia 
with  ether  and  for  nitrous-oxide-oxygen  anesthesia. 

After  a  preliminary  anesthesia  to  depress  the  laryngeal 
reflex  a  silk- woven  catheter,  about  No.  22  French,  is  inserted 
through  the  glottis  until  the  teeth  are  at  a  mark  26  cm.  from  its 
end.  Then,  with  a  bellows  or  pump,  operated  by  foot  or  power, 
the  air  is  passed  through  or  over  ether  in  a  bottle  into  the  trachea. 
The  gases  from  the  lungs  make  their  escape  around  the  catheter, 
and  this  should  be  small  enough  to  leave  ample  room  in  the 
glottis.  The  apparatus  should  bear  a  manometer  for  recording 
the  pressure,  and  the  positive  pressure  should  not,  in  ordinary 
operations,  exceed  10  mm.  of  mercury,  and  in  intrathoracic 
surgery  20  mm.  At  the  end  of  the  operation  the  ether  is  shut 
off,  and  air  insufflated  for  several  minutes.  From  three  to  six 
times  a  minute  the  air-stream  should  be  stopped  to  permit 
collapse  of  the  lungs  and  the  expulsion  of  some  C02,  which  tends 
to  collect  in  the  alveoli.  The  ether-air  vapor  should  be  of  about 
6  or  7  per  cent,  strength. 

The  patient  makes  light  respiratory  movements,  but  the 
oxygenation  of  the  blood  goes  on,  irrespective  of  respiration. 
The  color  of  the  skin  is  good,  and  the  pulse  is  normal.  If  the 
patient  vomits  on  the  table,  or  if  blood  runs  down  the  throat,  as 
in  mouth  operations,  the  positive  pressure  of  the  escaping  gases 
prevents  aspiration  of  the  foreign  material  into  the  lungs. 

Following  the  anesthesia  there  seem  to  be  no  bad  effects  from 
the  tube  or  the  ether  vapor,  either  upon  the  glottis,  the  trachea, 
the  bronch,  or  the  lungs,  even  in  the  presence  of  a  respiratory 
disease;  and  usually  there  is  no  nausea  or  vomiting.  There  have 
been  a  few  deaths  reported,  generally  due  to  rupture  of  the 
lungs  from  too  great  pressure,  or  to  puncture  of  the  trachea  by 
a  tube  that  is  too  long.  This  last  produces  interstitial  em- 
physema. These  dangers  can  be  eliminated  by  having  a  short 
tube,  a  manometer,  and  a  careful  anesthetist,  or  by  a  safety 
valve  set  at  20  mm.  of  pressure. 

Githens  and  Meltzer  (191 1)  showed  that  double  the  lethal 
dose  of  strychnine  given  under  ether  anesthesia  by  intratra- 
cheal insufflation  did  not  cause  the  death  of  a  single  animal. 

TREATMENT  OF  UNTOWARD  SYMPTOMS  IN  GENERAL 
ANESTHESIA 

(A)  Cyanosis. — If  this  is  due  to  excessive  secretion  or  the 
falling  back  of  the  tongue  or  jaw,  or  falling  of  the  paralyzed 
epiglottis,  so  as  to  act  as  a  valve  over  the  glottis,  or  turning  of 


294  PHARMACOLOGY  AND  THERAPEUTICS 

the  head  too  much  to  the  side,  the  condition  should  be  promptly- 
remedied.  If  there  is  respiratory  weakness,  the  anesthetic 
should  be  stopped  and  a  respiratory  stimulant,  such  as  caffeine 
or  atropine,  injected  hypodermatically.  In  the  laboratory  a 
dog  lightly  anesthetized  with  ether  or  chloroform  is  likely  to 
become  conscious  and  recover  his  reflexes  if  a  hypodermic  of 
caffeine  is  administered.  If  necessary,  artificial  respiration  and 
the  administration  of  oxygen  may  be  resorted  to. 

(B)  A  rapid,  weak,  or  irregular  pulse  suggests  the  withdrawal 
of  the  anesthetic  and  the  use  of  saline  by  rectum  or  intravenously. 

(C)  For  marked  collapse,  the  following  is  the  treatment: 

i.  If  from  ether,  lower  head,  raise  feet,  and  give  free  access 
of  air.  If  from  chloroform,  keep  body  level  or  may  precipitate 
heart  failure  (Bennett). 

2.  Keep  up  body  warmth,  using  hot  towels  and  hot  blankets. 

3.  Inject  hypodermatically  atropine,  caffeine,  or  camphor 
(not  ether  or  whisky).  Camphor  may  be  useful  in  chloroform 
collapse,  where  the  heart  is  the  organ  at  chief  fault.  (See  dis- 
cussion under  Camphor.) 

4.  If  an  ether  case,  give  hot  saline  by  rectum ;  or  an  intrave- 
nous infusion  of  about  400  c.c.  of  normal  saline  solution,  to  which 
may  be  added  10  minims  of  adrenaline  chloride  solution.  Con- 
tinuous slow  saline  infusion  for  half  an  hour  with  15  to  30  minims 
(1-2  c.c.)  of  adrenaline  chloride  solution  is  of  great  advantage. 
In  the  light  of  the  work  of  Le\y  and  Lewis,  adrenaline  would  be 
absolutely  contraindicated  in  chloroform  anesthesia  at  any  stage; 
yet  we  have  surgical  reports  of  excellent  results  from  adrenaline 
even  after  chloroform. 

5.  If  necessary,  the  limbs  may  be  bandaged  from  fingers  and 
toes  up,  or  Crile's  pneumatic  suit  applied. 

6.  Artificial  respiration  and  the  administration  of  oxygen 
and  carbon  dioxide.  Henderson  says  that  carbon  dioxide  should 
not  be  given  in  concentration  above  6  per  cent.  Meltzer's 
method  of  artificial  respiration  by  intratracheal  insufflation  or 
by  a  suitable  mouth-cap  may  be  employed. 

7.  //  the  heart  stops,  try  rhythmic  thumping  or  pressure  over 
the  heart,  or  rhythmic  pressure  at  a  rate  of  30  per  minute  in  the 
epigastrium;  in  an  abdominal  operation  massage  heart  through 
the  diaphragm.  With  a  long  thin  needle  inject  10  minims  of 
adrenaline  solution  and  10  minims  of  the  tincture  of  digitalis 
into  the  cavity  of  the  ventricle,  and  massage  vigorously.  The 
author  has  resuscitated  dogs  in  this  manner.  This  should  not 
be  attempted  if  the  heart  is  beating. 

Ether,  whisky,  and  strychnine  hypodermatically  have  re- 
peatedly been  shown  to  increase  the  collapse,  and  electricity  to 


NITROUS    OXIDE  295 

produce  fibrillation  and  stoppage  of  a  weak  heart.  In  chloroform 
collapse  the  heart  is  very  feeble,  so  that  measures  to  increase  the 
peripheral  resistance  must  be  instituted  with  caution.  Bennett 
says,  "do  not  lower  the  head  end  of  the  body." 

Therapeutics. — The  objects  of  general  anesthesia  are:  to 
abolish  pain,  to  abolish  consciousness,  and  to  relax  muscle. 
General  anesthesia  may  be  employed: 

1.  In  surgical  cutting  operations. 

2.  To  set  a  fracture. 

3.  To  reduce  a  dislocation. 

4.  To  reduce  a  hernia.  » 

5.  To  permit  more  thorough  examination  for  diagnosis  of 
the  abdomen  or  an  injured  limb. 

6.  To  stop  convulsions  (tetanus,  strychnine  poisoning). 

7.  In  labor — at  the  time  of  the  expulsion  of  the  fetal  head  to 
stop  pain  (perineal  pain)  and  lessen  or  abolish  the  contractions 
of  the  uterus.  As  a  rule,  only  enough  chloroform  is  required 
for  this  to  well  wet  the  chloroform  mask.  General  anesthetics 
tend  to  lessen  the  power  of  the  uterus  to  contract,  hence  to  some 
extent  favor  postpartum  hemorrhage.  Postpartum  operations 
are  preferably  done  under  ether. 

NITROUS    OXIDE 

Nitrous  oxide,  N20,  or  laughing-gas,  is  obtained  by  heating  a 
mixture  of  salts  containing  ammonium  nitrate.  It  is  marketed 
under  compression  in  steel  cylinders,  and  is  administered  by  a 
special  inhaler,  consisting  of  a  rubber  bag  and  mouth-piece  with 
exit  valves  for  the  expired  air.  It  received  the  name  of  laughing- 
gas,  because  in  some  instances  the  inhalation  of  a  small  quantity 
of  it  produced  uncontrollable  hilarity.  A  bright,  glowing  stick 
plunged  into  nitrous  oxide  ionizes  it,  and  bursts  into  bright  flame, 
as  in  pure  oxygen ;  but  a  dull  glowing  stick  goes  out  and  animals 
and  plants  quickly  die  if  placed  in  the  gas,  for  they  cannot  bring 
about  dissociation  to  obtain  the  oxygen.  So  nitrous  oxide  will 
not  maintain  life,  and  if  used  pure,  quickly  produces  asphyxia. 
It  must,  therefore,  be  given  with  air  or  oxygen.  It  has  no  local 
action,  and,  after  absorption,  exists  in  simple  solution  in  the  blood 
plasma.  But  it  is  not  an  indifferent  gas,  like  nitrogen,  for  in 
85  or  90  per  cent,  strength  it  is  a  distinct  narcotic,  capable  of 
producing  very  rapidly  a  full  degree  of  unconsciousness,  though 
with  incomplete  muscular  relaxation.  Some  of  the  anesthesia 
has  been  attributed  to  asphyxia,  but  not  only  is  asphyxia  not 
necessary  in  the  anesthesia,  but  it  is  to  be  avoided  as  much  as 
possible.  When  air  is  used  as  the  diluent,  there  is  always  some 
asphyxia,  with  venous  congestion,  cyanosis,  and  raised  blood- 


296  PHARMACOLOGY  AND  THERAPEUTICS 

pressure ;  so  to  maintain  anesthesia  it  is  now  regularly  employed 
with  oxygen  as  the  diluent.  Gatch  states  that  it  is  best  and 
cheapest  not  to  admit  any  air  at  all;  and  Teter  says  it  is  impossible 
to  avoid  asphyxia  with  less  than  11  per  cent,  of  oxygen. 

With  the  nitrous-oxide-oxygen  combination  the  production  of 
anesthesia  is  very  prompt,  and  the  recovery  almost  immediate. 
To  produce  the  anesthesia  it  may  be  necessary  to  add  some  ether. 
And  it  requires  such  skill  to  keep  the  patient  in  a  uniform  state  of 
anesthesia  of  sufficient  degree  without  asphyxia  that  it  is  custom- 
ary to  administer,  about  half  an  hour  before,  some  slowly  act- 
ing narcotic,  such  as  morphine  sulphate.  Gatch  has  introduced 
a  method  of  rebreathing  which  not  only  saves  gas,  but  utilizes 
the  patient's  own  carbon  dioxide  for  the  double  purpose  of 
stimulating  the  respiratory  center  and  preventing  acapnia.  An 
excess  of  carbon  dioxide  shows  by  rapid  forced  respiratory  efforts, 
followed  by  sweating,  livid  appearance,  gradual  slowing  of  the 
pulse,  and  finally  cessation  of  respiration.  The  three  danger- 
signals  in  the  administration  are  vomiting,  cyanosis,  and  slow 
pulse. 

According  to  Crile,  with  the  same  degree  of  trauma  there  is 
only  one-fourth  as  much  shock  from  nitrous  oxide  as  from  ether. 
So  the  method  is  an  admirable  one  in  the  hands  of  an  expert. 
It  is  not  satisfactory,  however,  in  alcoholics,  the  obese,  and 
robust  athletic  persons.  It  is  contraindicated  in  children  under 
five  years,  because  of  the  ease  with  which  asphyxia  can  be  pro- 
duced in  such;  in  old  people  with  degenerative  lesions,  because 
of  the  high  blood-pressure  and  because  of  the  convulsive 
movements  in  case  of  asphyxia ;  usually  in  brain  surgery  because 
of  increased  venous  flow;  and  in  cardiac  weakness  because  of 
the  raised  peripheral  resistance. 

The  nitrous  oxide  and  oxygen  combination  has  come  into 
considerable  use  as  the  anesthetic  of  choice  for  general  purposes. 
Nitrous  oxide  and  air  are  still  much  employed  by  dentists  in  the 
extraction  of  teeth,  and  by  anesthetists  as  a  preliminary  to  ether 
to  avoid  the  disagreeable  first  and  second  stages. 

ETHYL  CHLORIDE 

Ethyl  chloride  (a^thylis  chloridum),  C2H5C1,  is  a  highly  vola- 
tile and  inflammable  gas,  prepared  by  the  action  of  hydrochloric 
acid  upon  absolute  alcohol.  It  condenses  to  a  liquid  at  130  C. 
(5 5. 4°  F.),  and  is  kept  thus  in  sealed  tubes  under  pressure.  These 
tubes  are  made  with  a  minute  pin-hole  nozle  covered  with  a  cap, 
and  on  removal  of  this  cap  the  liquid  issues  with  some  force  in  the 
form  of  a  very  fine  spray. 

Local  Action. — On  striking  the  warm  skin  it  vaporizes  with 


ALCOHOL  297 

such  rapidity  that  it  freezes  the  tissues.  This  makes  a  local 
anesthesia  of  a  moment's  duration,  during  which  a  small  cut,  as 
of  an  abscess  or  infected  finger,  or  a  puncture,  as  in  paracentesis 
of  thorax  or  abdomen,  may  be  made  without  pain.  The  freezing 
of  the  tissues  sometimes  results  in  sloughing.  The  spray  is 
sometimes  also  employed  in  facial  neuralgia. 

Systemic  Action. — To  produce  general  anesthesia  ethyl 
chloride  is  vaporized  into  an  inhaler.  The  patient  may  be 
brought  into  a  state  of  anesthesia  in  from  one  to  two  minutes 
without  any  local  irritation ,  but  with  incomplete  muscular  relaxa- 
tion. Recovery  when  the  anesthetic  is  stopped  is  almost  imme- 
diate, and  because  of  this  it  is  a  difficult  task  to  maintain  the 
anesthesia  for  any  length  of  time.  (Whiteford  has  kept  the 
patient  under  ethyl  chloride  for  thirty-five  minutes,  and  Wiessner 
for  fifty  minutes,  by  pouring  2  or  3  c.c.  on  the  mask  every  two 
minutes;  Montgomery  and  Bland,  for  fifty- four  minutes.)  A 
few  fatalities  have  been  reported,  but,  according  to  W.  Lauzun- 
Brown  (Hospital,  October  27,  1906),  these  occurred  in  the  early 
days  of  its  use.  Since  then  more  than  7000  operations  have 
been  performed  under  its  administration  at  the  Central  London 
Throat  and  Nose  Hospital  without  any  death.  Ware  has  used 
it  in  8000  cases,  and  recently  Sill  has  reported  its  employment 
with  an  Improved  Ware  Inhaler,  in  500  tonsil  and  adenoid  cases 
without  untoward  symptoms.  He  says  that  it  takes  two  to  five 
minutes  to  produce  anesthesia  sufficient  for  the  removal  of  ade- 
noids and  tonsils,  but  the  recovery  is  almost  immediate,  so  that 
the  child  can  cough  and  expectorate  the  blood  and  adenoid  tissue. 
Vomiting  after  the  anesthesia  is  not  uncommon. 

On  the  average,  5  gm.  will  produce  unconsciousness  and 
abolition  of  pain  in  one  or  two  minutes,  and  maintain  it  for  ten 
minutes,  but  the  reflexes  are  not  depressed  to  the  point  of  com- 
plete muscular  relaxation.  Because  of  its  concentrated  form 
and  ease  of  transportation,  it  being  a  liquid  in  glass  tubes,  and 
because  of  its  cheapness  in  the  dose  used,  it  has  been  employed 
in  operations  of  short  duration,  in  dentistry,  and  as  a  preliminary 
to  ether  anesthesia. 

Ethyl  bromide  resembles  ethyl  chloride  in  its  action,  but  is 
not  quite  so  volatile,  and  its  use  has  been  abandoned. 

Intoxicants 

alcohol 

Common  alcohol,  grain  alcohol,  ethyl  alcohol,  C2H5(OH), 
is  made  by  fermenting  a  sugar  solution  with  yeast  in  the  presence 
of  nitrogenous  substances.     The  sugar  may  be  that  of  a  fruit- 


298  PHARMACOLOGY   AND   THERAPEUTICS 

juice,  or  that  prepared  from  starch  or  wood.  Along  with  the 
ethyl  alcohol  other  bodies  are  produced.  The  alcohol  of  com- 
merce is  obtained  by  distillation,  and  contains  amyl  alcohol  and 
other  bodies  which  constitute  its  "fusel  oil."  It  mixes  freely 
with  water,  ether,  and  chloroform,  and  is  a  solvent  for  alkaloids, 
many  salts,  resins,  volatile  oils,  and  two  of  the  fixed  oils,  viz., 
castor  oil  and  croton  oil.  It  does  not  dissolve  the  other  fats  and 
fixed  oils,  or  adhesive  plaster  or  collodion. 

Preparations. — Pure  alcohol  is  to  be  had  in  three  strengths, 
viz. : 

(a)  Absolute  alcohol,  at  least  99  per  cent,  of  ethyl  alcohol; 
(b)  Alcohol,  95  per  cent.  (U.  S.  P.,  94.9)  by  volume.  This  is  not 
the  alcohol  of  commerce,  but  is  known  to  the  trade  as  "deodorized 
alcohol"  or  "cologne  spirit."  It  is  ordinary  grain  alcohol 
with  the  fusel  oil  removed,  and  has  a  specific  gravity  of  0.816  at 
6o°  F.  (c)  Diluted  alcohol,  48.9  per  cent,  by  volume,  made 
with  equal  volumes  of  water  and  alcohol,  which  shrink  on  mixing. 

For  internal  use,  one  or  other  of  the  alcoholic  drinks  is  regu- 
larly employed,  rather  than  pure  alcohol;  and  these  contain,  in 
addition  to  the  alcohol,  substances  which  give  them  their  char- 
acteristic odor  and  taste.  A  large  number  of  pharmaceutic 
preparations  contain  alcohol  either  as  solvent  or  preservative, 
and  certain  proprietary  remedies  with  a  large  content  of  alcohol 
are  especially  popular.  Women  habitues  frequently  drink  in 
secret,  and  may  consume  large  quantities  of  eau  de  cologne, 
Florida  water,  witch-hazel,  or  some  proprietary  remedy.  De- 
natured alcohol,  for  use  tax  free,  is  a  mixture  of  100  parts  of  high- 
proof  grain  alcohol,  10  parts  of  rectified  wood-alcohol,  and  0.5 
part  of  benzin. 

The  alcoholic  drinks  in  common  use  are  of  five  classes: 

1.  The  malt  liquors. 

2.  The  red  and  white  wines. 

3.  The  fortified  wines. 

4.  The  distilled  liquors,  or  spirits. 

5.  The  elixirs. 

1.  The  malt  liquors  are  prepared  from  starchy  substances, 
usually  grain.  The  grains  are  ground  and  boiled  with  water  to 
form  a  mash,  i.  e.,  to  hydrolyze  the  starch  and  form  a  starch  paste. 
On  the  addition  of  barley  malt,  which  contains  the  ferment  dias- 
tase, the  starch  changes  and  goes  into  solution  as  dextrin,  mal- 
tose, and  dextrose.  To  this  solution  are  added  hops,  which  yield 
a  bitter  principle  and  a  hypnotic  substance;  then,  after  filtration, 
the  liquid  is  fermented  by  yeast  to  the  desired  degree.  Then  the 
yeast  is  killed  by  heat,  the  fermentation  being  always  stopped 


ALCOHOL  299 

before  all  the  sugars  are  destroyed.  Cheap  beers  have  quassia, 
gentian,  wormwood,  or  other  bitter  substitutes  for  the  hops. 

The  malt  liquors  contain  from  3  to  7  per  cent,  of  alcohol  by 
volume,  together  with  about  the  same  percentage  of  extractive 
matter,  composed  of  dextrin,  maltose,  and  colloidal  material, 
and  acids  of  the  fatty  series,  chiefly  acetic.  They  all  contain 
CO2  gas,  so  are  effervescent.  Strauss  states  that  they  average 
about  0.145  gm-  °f  purin  bodies  per  liter.  They  are  acid  in 
reaction,  have  the  action  of  bitters  upon  the  appetite,  and  are 
nutritive.  In  the  stomach  they  immediately  set  free  the  con- 
tained C02.  The  sugar  bodies  also  tend  to  generate  gas,  and  the 
colloidal  material  to  interfere  with  the  activity  of  the  digestive 
ferments.  None  of  the  malt  liquors  are  official,  but  those  in 
common  use  are:  Beer,  ale,  porter,  and  stout. 

Beers  (''lager  beer")  are  prepared  by  slow,  cool  fermentation 
(380  F.) — Blyth  says  i2°-i4°  C.  (53°-57°),  by  bottom  yeast, 
i.  e.,  a  yeast  which  sinks.  Imported  beer  is  usually  stronger 
than  domestic,  a  little  higher  proportion  of  alcohol  being  desired 
for  preservation  purposes. 

Ales  (in  British  countries  called  "beer")  are  fermented  at 
ordinary  temperatures  (56°-68°  F.)  by  top  yeast,  i.  e.,  a  yeast 
that  floats.     They  average  somewhat  more  alcohol  than  beer. 

Porter  and  stout  are  ales  in  which  the  malt  has  been  highly 
kilned  or  roasted,  so  that  some  of  it  is  changed  to  caramel.  As  a 
consequence  they  have  a  very  dark  color  and  a  caramel  taste, 
and  are  rich  in  dissolved  substances.  Stout  is  the  richer  and 
stronger  of  the  two. 

The  liquid  extracts  of  malt  used  in  medicine  are  beers  contain- 
ing a  small  percentage  of  alcohol,  a  large  amount  of  nutritive 
extractive,  chiefly  sugars,  and  unchanged  extract  of  malt. 

2.  The  wines  are  made  by  yeast  fermentation  of  saccharine 
fruit-juices.  They  vary  considerably  in  their  composition,  but 
regularly  contain  from  8.5  to  15  per  cent,  of  alcohol  by  volume, 
with  glycerin,  tartaric  acid,  acetic  and  other  fatty  acids,  alde- 
hydes, furfurol,  amylic,  cenanthylic,  and  other  alcohols,  certain 
esters  which  are  produced  on  long  standing  and  give  to  the  wine 
its  mellowness  and  bouquet,  and  albuminous  and  other  colloidal 
extractive  matters.  The  red  wines  contain  tannic  acid;  the 
sweet  wines  contain  dextrose.  Kahlbaum  of  Berlin  has  separated 
12  different  esters  from  wines  in  common  use,  acetic  ether  being 
that  most  frequently  encountered.  Wines  are  not  so  nutritive 
as  the  malt  liquors,  and  many,  such  as  claret.  Burgundy,  Rhine, 
and  Moselle  wines,  contain  little  or  no  sugar.  With  age  the 
tannin,  alcohol,  and  acids  decrease,  and  the  glycerin  and  esters 
increase.     The  largest  percentage  of  esters  is  0.3  (Dupre). 


300  PHARMACOLOGY   AND    THERAPEUTICS 

A  sweet  wine  is  one  that  contains  free  sugar;  a  dry  wine  is  one 
that  is  free  from  sugar,  practically  all  the  sugar  having  been 
changed  in  the  fermentation.  A  light  wine  is  one  that  contains 
a  low  proportion  of  alcohol;  a  strong  or  heavy  wine,  one  that  is 
strong  in  alcohol.  A  sparkling  wine  is  one  that  contains  C02  in 
solution,  as  champagne  and  sparkling  Burgundy;  these  wines 
bubble  or  effervesce  when  the  cork  is  withdrawn,  and  because  of 
the  C02  gas,  are  often  readily  borne  in  cases  of  refractory  vomit- 
ing. 

The  Pharmacopoeia  recognizes  red  wine  (vinum  rubrum) 
and  white  wine  (vinum  album). 

Red  wine  is  prepared  by  fermenting  the  juice  of  red  grapes  in 
the  presence  of  their  skins.  It  contains  tannic  acid,  and  is 
more  astringent  than  white  wine.  Claret  is  a  common  red  wine, 
which,  because  of  its  astringency,  is  sometimes  used  as  a  gargle 
in  sore  throat. 

White  wine  is  made  from  grapes  that  have  been  freed  from 
seeds,  stems,  and  skins.  It  usually  does  not  contain  tannic  acid. 
Sauterne  and  Chablis  are  examples. 

Fermented  apple  and  pear  ciders  are  of  the  class  of  wines, 
as  they  are  prepared  from  sugar-containing  fruit-juices.  They 
contain  much  malic  acid  and  usually  sugar,  and  a  large  quantity 
of  extractive  matter. 

3.  The  fortified  wines  are  certain  wines  whose  percentage  of 
alcohol  has  been  increased  by  the  addition  of  a  distilled  liquor 
made  from  grapes,  raisins,  figs,  or  sweet  potatoes.  In  ordinary 
fermentation  the  yeast  activity,  even  under  the  most  favorable 
conditions,  ceases  altogether  at  about  15  to  17  per  cent,  of  alcohol 
by  volume,  so  that  this  is  the  limit  of  strength  to  be  obtained  by 
simple  fermentation.  The  fortified  wines  have  a  strength  be- 
tween this  and  that  of  the  distilled  liquors. 

Sherry  (vinum  xericum),  port  (vinum  portense),  and  Madeira 
are  the  common  fortified  wines,  and  they  contain  from  17  to  25 
per  cent,  of  alcohol  by  volume.  Sherry  is  quite  acid,  and  con- 
tains little  or  no  sugar.  Port  is  less  acid,  but  has  from  3  to  7  per 
cent,  of  sugar. 

4.  Distilled  liquors,  or  spirits,  are  prepared  by  distilling  any 
fermented  liquor.  By  the  distillation  the  sugars,  the  non-vola- 
tile acids,  and  extractive  matters  are  left  behind,  and  the  alcohols, 
the  ethers,  and  any  volatile  acids  are  distilled  over.  On  long 
standing  the  alcohols  and  acids  react  upon  each  other  and 
develop  the  esters,  which  give  the  liquor  its  bouquet.  The 
Pharmacopoeia  recognizes  whisky  and  brandy.  The  distilled 
liquors  are  separated  into  two  general  classes,  according  to 
their  origin,  viz. : 


ALCOHOL  301 

(a)  Those  Obtained  from  Malt  Liquors. — In  common  use  are 
whisky  and  gin.  ("Schnaaps,"  in  Europe,  is  prepared  from 
potatoes,  and  is  a  cheap  whisky;  in  this  country  it  is  a  name 
employed  by  foreigners  for  corn  whisky.) 

Whisky  (spiritus  frumenti)  is  described  in  the  Pharmacopoeia 
as  "an  alcoholic  liquid  obtained  by  the  distillation  of  the  mash 
of  fermented  grain  (corn,  rye,  wheat,  barley),  and  not  less  than 
four  years  old.  It  contains  44  to  55  per  cent,  by  volume  of 
ethyl  alcohol,  and  in  addition  minute  quantities  of  various  other 
alcohols,  ethers,  etc.,  carried  over  in  the  distillation,  and  acid 
esters  formed  on  standing."  Cheap  whiskies  are  aged  by  ozone 
and  electricity  in  three  days,  and  are  darkened  with  prune-juice 
to  give  them  the  color  that  is  properly  derived  from  storage  in 
oak  barrels.  The  fusel  oil  of  whisky  is  composed  chiefly  of  amyl 
alcohol  and  furfurol. 

Scotch  and  Irish  whiskies  have  a  somewhat  smoky  odor  from 
being  distilled  over  peat  fires,  or  being  made  from  malt  that  is 
dried  over  peat  fires.  They  are  said  to  contain  traces  of  creosote 
and  other  empyreumatic  oils.  Irish  whiskies  usually  contain  a 
rather  high  percentage  of  alcohol. 

Gin  is  prepared  by  distillation  of  fermented  rye  mash,  and 
redistillation  of  the  product  with  juniper  berries,  or  sometimes 
other  aromatics,  such  as  cardamom  or  coriander.  It  contains  a 
high  percentage  of  alcohol,  60  to  70  per  cent.,  and  some  volatile 
oil  of  juniper,  on  account  of  which  it  is  diuretic  and  carminative. 
It  is  a  favorite  remedy  among  women  for  dysmenorrhea.  Gin  is 
sometimes  called  the  "compound  spirit  of  juniper." 

(b)  Those  Distilled  from  Fermented  Saccharine  Fruit-juices. — 
These  are  known  as  brandies.  Apple-brandy  and  pear-brandy 
are  prepared  from  apples  or  pear  cider.  But  the  brandy  of 
commerce  and  of  the  Pharmacopoeia  is  that  from  grape-wine. 
It  is  known  also  as  "  Cognac  "  or  "  French  brandy." 

Brandy  (spiritus  vini  gallici)  is  described  by  the  Pharmaco- 
poeia as  "an  alcoholic  liquid  obtained  by  the  distillation  of  the 
fermented,  unmodified  juice  of  fresh  grapes,  and  not  less  than  four 
years  old.  It  contains  46  to  55  per  cent,  by  volume  of  ethyl 
alcohol,  besides  enanthic  and  other  esters." 

Rum  is  the  distillate  from  fermented  molasses,  and  has  a 
slight  taste  of  brown  sugar.  It  varies  greatly  in  strength,  but  is 
frequently  much  stronger  than  brandy. 

5.  The  elixirs  are  aromatic,  sweetened,  hydro-alcoholic 
liquids.  They  are  artificial  mixtures,  and  contain  various  flavor- 
ing substances,  sugar,  and  a  large  percentage  of  alcohol.  They 
include  the  pharmaceutic  elixirs,  and  the  liqueurs,  cordials, 
crimes,  etc. 


3<D2  PHARMACOLOGY   AND    THERAPEUTICS 

The  following  table  of  percentages,  calculated  to  volume 
from  Hutchinson's  report,  gives  an  idea  of  their  alcohol  and 
sugar  content: 

Alcohol  Cane-sugar 

Chartreuse 50  per  cent,  by  volume  34  per  cent. 

Creme  de  menthe ,.  .  .  50    "       "       "        "  27    "      " 

Benedictine    60    "       "       "        "  32    "      " 

Absinthe *rillfc    .  .67    "       "       "       "  


Drinks  which  contain  much  absinthe,  as  absinthe  cordial  (and 
even  perhaps  Vermouth  wine),  have  a  peculiar  action  upon  the 
brain,  and  their  habitual  use  leads  to  mental  depression,  epilepti- 
form convulsions,  and  a  state  of  insanity.  Belgium,  Holland, 
France,  and  Switzerland  have  passed  laws  prohibiting  the  manu- 
facture of  absinthe  cordial,  and  since  October  1,  191 2,  the  United 
States  has  forbidden  its  importation. 

None  of  the  elixirs  are  employed  for  the  administration  of 
alcohol  as  medicine,  but  the  pharmaceutic  elixirs,  which  contain 
from  25  to  35  per  cent,  of  alcohol,  are  employed  as  vehicles  for 
bitter  and  bad-tasting  drugs.  The  elixir  of  calisaya  is  a  favorite 
soda-fountain  tipple. 

There  are  three  official  elixirs: 

Elixir  aromaticum,  aromatic  elixir  (compound  spirit  of 
orange,  1.2;  syrup,  37.5;  alcohol,  about  25  per  cent.,  and  water 
to  make  100).     It  is  used  solely  as  a  flavored  vehicle. 

Elixir  adjuvans — aromatic  elixir,  containing  12  per  cent,  of 
fluidextract  of  glycyrrhiza.  It  is  used  solely  as  a  flavoring 
vehicle.     The  licorice  is  incompatible  with  acids. 

Elixir  of  the  phosphates  of  iron,  quinine,  and  strychnine.  (See 
Strychnine.) 

In  addition  to  the  above,  the  following  mixed  drinks  are 
worthy  of  note : 

A  highball  is  whisky  diluted  with  a  carbonated  water.  Some- 
times lemon-peel  is  added. 

A  cocktail  is  an  aromatic  or  bitter,  strongly  alcoholic,  mixed 
drink,  to  be  taken  before  meals  as  an  appetizer.  Its  basis  is 
usually  gin. 

A  milk-punch  is  a  mixture  of  sugar,  milk,  and  whisky,  served 
cold.  It  may  have  a  little  nutmeg  sprinkled  over  its  surface.  Its 
flavor  is  improved  by  a  dash  of  Jamaica  rum. 

A  brandy  milk-punch  is  made  with  brandy  instead  of  whisky. 

An  egg-nog  is  a  milk-punch  shaken  up  with  an  egg  and  cracked 
ice,  and  strained. 

It  must  be  borne  in  mind  that  most  liquid  pharmaceutic 
preparations  contain  alcohol,  and  some  of  them  are  nearly  all 


ALCOHOL  303 

alcohol.  Many  of  the  nutritive  peptone  mixtures  on  the  market 
(panopepton,  liquid  peptonoids,  etc.)  owe  much  of  their  nutritive 
value  to  the  15  or  20  per  cent,  of  alcohol  present. 

The  medicinal  dose  of  a  distilled  liquor  is  4  drams  (15  c.c.), 
that  of  sherry  or  port,  about  twice  as  much.  A  sherry-glass  holds 
1  ounce  (30  c.c). 

Pharmacologic  Action. — Having  a  great  affinity  for  water 
and  being  a  coagulant  of  protein,  alcohol  tends  to  irritate  and 
destroy  cells.     It  is,  therefore,  a  general  protoplasmic  poison. 

Micro-organisms. — In  the  preparation  of  alcoholic  liquors 
by  fermentation  it  is  found  that  the.  activity  of  the  yeast  life  is 
retarded  when  the  alcohol  reaches  about  10  per  cent,  of  the 
liquid,  and  is  completely  checked  when  the  alcohol  is  about 
15  per  cent.  Typhoid  bacilli  were  completely  destroyed  in 
twelve  hours  in  a  mixture  of  equal  parts  of  red  wine  (12  per  cent.) 
and  water  (Sabrazes  and  Marcandier).  It  is  evident,  there- 
fore, that,  when  its  application  is  prolonged,  alcohol  has  anti- 
septic properties.  Harrington  and  Walker  found  that  a  solution 
of  about  70  per  cent,  strength  has  a  greater  germicidal  power  than 
stronger  solutions.  Strong  alcohol  (60  to  90  per  cent.)  has  been 
used  for  the  preservation  of  plant  and  animal  specimens. 

Skin. — Applied  to  the  skin  and  allowed  to  evaporate  freely 
it  is  cooling,  and  tends  to  harden  the  skin  and  to  check  sweating. 
If  not  allowed  to  evaporate,  as  when  covered  with  flannel'  or 
used  on  a  compress,  it  is  counterirritant,  producing  dilatation 
of  the  vessels,  with  warmth  and  reddening. 

To  mucous  membranes  and  raw  tissues  it  is  irritant  and  as- 
tringent, for  it  abstracts  water  from  the  superficial  cells  and 
coagulates  their  protoplasm.  On  account  of  this,  strong  liquors 
for  internal  use  should  be  well  diluted.  Hertz  says  that  contact 
of  alcohol  with  any  part  of  the  digestive  canal  gives  rise  to  a 
sensation  of  heat. 

The  power  to  coagulate  protoplasm  gives  alcohol  its  value  as 
a  hardening  agent  for  anatomic  specimens. 

Alimentary  Tract. — A  chemic  substance  possessing  such 
striking  solvent  powers  and  affinities  requires  separate  considera- 
tion for — (a)  Its  effects  on  the  chemistry  of  the  contents  of  the 
stomach;  (b)  its  effects  on  the  stomach-wall;  and  (c)  its  effects 
on  the  stomach  functions.  It  is  well  to  remember  also  that  its 
local  action  depends  upon  the  degree  of  its  dilution,  rather  than 
upon  the  actual  amount  of  alcohol  involved. 

1.  Action  on  the  Chemistry  of  the  Stomach-contents. — Experi- 
ments in  vitro  indicate  that  50  per  cent,  alcoholic  liquids,  such  as 
whisky  or  brandy  undiluted,  will  precipitate  the  proteins  of 
food,  will  to  some  extent  precipitate  pepsin,  and  will  check  the 


304  PHARMACOLOGY   AND   THERAPEUTICS 

activity  of  the  digestive  process.  But  by  alcoholic  liquids  below 
20  per  cent,  in  strength  pepsin  in  solution  is  not  injured,  and  when 
the  proportion  of  alcohol  present  does  not  exceed  10  per  cent.,  or 
perhaps  even  15  per  cent.,  the  effect  upon  proteins  and  upon  the 
activity  of  the  digestive  ferments  in  the  test-tube  is  practically 
negative.  Solutions  up  to  2  per  cent,  in  strength  have  been 
shown  by  Chittenden,  Mendel,  and  Jackson  to  favor  the  activity 
of  pepsin  digestion. 

But  with  alcohol  there  is  a  great  difference  between  the 
actions  in  a  test-tube  and  those  in  the  stomach;  for  in  the  test- 
tube  the  alcoholic  strength  remains  the  same  throughout  the 
experiment,  and  the  products  of  digestion  are  not  removed, 
while  in  the  stomach  the  products  of  digestion  pass  away  and  the 
alcohol  strength  becomes  steadily  less,  owing  to  dilution  with 
gastric  juice  and  mucus  and  to  absorption  of  the  alcohol.  We 
are  safe  in  saying,  therefore,  that  in  the  human  alimentary  tract 
the  influence  of  moderate  quantities  of  properly  diluted  alcohol  upon 
the  chemic  processes  of  digestion  is  a  negligible  factor. 

With  the  alcoholic  drinks,  however, — and  it  is  these  and  not 
pure  alcohol  that  are  in  common  use  both  in  therapeutics  and 
as  beverages, — the  other  constituents  must  be  taken  into  con- 
sideration. The  volatile  constituents  of  wines  have  been 
studied  by  Krantwig  and  Vogel  (Binz),  and  found  to  have  a 
pharmacologic  action  similar  to  that  of  alcohol.  Their  propor- 
tion, however,  is  very  small.  Chittenden  and  Mendel  have 
determined  that  the  distilled  liquors,  which  contain  the  same  or 
similar  volatile  substances,  exert  an  effect  upon  the  digestive 
chemistry  practically  proportional  to  the  amount  of  their  alco- 
hol. Hence  if  the  distilled  liquors  are  diluted  to  10  per  cent., 
they  have  no  harmful  effect  on  the  chemistry  of  digestion. 

But  Chittenden  and  Mendel  found  that  the  wines  and  malt 
liquors  tend  to  retard  pepsin  digestion,  even  when  their  alcohol 
is  much  below  the  harmful  percentage,  so  if  taken  in  considerable 
quantity  they  are  deleterious  to  digestion.  This  is  because  of 
their  organic  acids  and  colloidal  constituents,  and  not  because 
of  their  alcohol.  Red  wines,  because  of  their  tannic  acid,  which 
tends  to  precipitate  protein,  have  a  retarding  influence  beyond 
that  of  white  wines. 

2.  Action  on  the  Structures  of  the  Stomach-wall. — As  it  cannot 
evaporate  from  the  stomach,  alcohol  dilates  the  vessels  and  gives 
a  feeling  of  warmth  in  the  stomach.  Below  a  strength  of  10 
per  cent,  it  has  practically  no  other  effect  unless  taken  in  too 
large  quantities  to  be  absorbed  rapidly.  But  in  strength  above 
50  per  cent.,  and,  to  many  stomachs,  in  much  weaker  dilution, 
it  is  powerfully  irritant  and  capable  of  causing  inflammatory 


ALCOHOL 


305 


changes.     Its  local  irritant  properties  depend  on  its  dilution 
rather  than  on  the  actual  amount  of  alcohol  involved. 

3.  Action  on  the  Functions  of  the  Stomach. — The  chief  func- 
tions are  absorption,  motility,  and  secretion. 

(a)  Absorption. — Ordinary  amounts  of  alcohol  in  proper  dilu- 
tion are  quickly  absorbed,  and  will  usually  have  disappeared 
from  the  stomach  in  less  than  half  an  hour  (Cushny  says  20  per 
cent,  absorbed  by  stomach  and  80  per  cent,  from  intestine.) 
But  during  a  meal  an  amount  of  alcohol  can  be  ingested  without 
systemic  effects  that,  if  taken  before  the  meal,  i.  e.,  on  an  empty 
stomach,  would  produce  distinct  feelings  or  manifestations  of 
intoxication.  This  is  a  fact  that  is  well  known  to  the  laity,  and 
the  difference  is  due  to  admixture  with  the  food  and  the  conse- 
quent retardation  of  absorption.  The  effect  of  alcohol  on  the 
absorption  of  other  substances,  such  as  digestive  products, 
water,  and  drugs,  is  favorable,  unless  the  alcohol  is  present  in 
strength  great  enough  to  injure  the  cells  of  the  mucous  mem- 
brane or  to  produce  a  coating  of  thick  mucus,  or  to  act  as  an 
astringent,  i.  e..  in  a  strength  above  about  20  per  cent. 

(b)  Motility. — Kast's  experiments  with  alcohol  up  to  20  per 
cent,  strength  indicated  increased  motility;  those  of  Gluzinski 
show  retarded  motility.  From  an  experimental  point  of  view, 
therefore,  the  effect  on  motility  remains  undecided.  Yet, 
clinically,  alcohol  seems  to  increase  the  motor  functions,  for 
solutions  containing  above  20  per  cent,  and  the  distilled  liquors, 
even  when  diluted  to  20  per  cent.,  are  prompt  and  powerful 
carminatives. 

(c)  Secretion. — 1.  The  Secretion  of  Saliva  and  Mucus. — In 
the  mouth  these  are  increased  by  strong  alcohol,  as  with  other 
irritants,  the  resulting  secretion  being  for  protective  purposes. 

In  the  stomach,  also,  50  per  cent,  alcohol,  as  in  a  distilled 
liquor,  quickly  results  in  the  secretion  of  a  protecting  coat  of 
thick,  tenacious  mucus.  This  not  only  protects  the  mucous 
membrane  from  further  injury  by  the  alcohol,  but  by  retarding 
absorption  serves  to  protect  the  liver  and  to  lessen  the  systemic 
effects. 

2.  The  Secretion  of  Gastric  Juice. — We  are  able  to  divide  the 
action  of  alcohol  and  alcoholic  drinks  upon  this  secretion  into 
three  distinct  periods,  viz. : 

1.  The  period  of  excitation  of   the  taste-buds  or  olfactory 

nerves  to  produce  appetite. 

2.  The  period  during  which  the  alcohol  is  in  the  stomach. 

3.  The  period  after  absorption  while  the  alcohol  is  in  the 

circulating  blood. 
First    Period. — Pawlow's    work    established    the    fact    that 


306  PHARMACOLOGY   AND    THERAPEUTICS 

appetite  is  of  great  importance  in  the  production  of  the  first 
gastric  juice,  the  so-called  "appetite  juice,"  or  "psychic  gastric 
juice."  In  experiments  with  dogs  he  noticed  that  a  number  of 
substances,  for  example,  white  of  egg,  will  remain  absolutely 
undigested  if  placed  in  the  stomach  without  the  knowledge  of  the 
animal;  but  that  if  then  his  appetite  is  stimulated,  as  by  the 
sight  or  smell  of  food,  the  white  of  egg  is  soon  digested  because 
of  the  appearance  of  gastric  juice.  Hence  alcoholic  drinks  which 
promote  the  appetite,  whether  palatable  wines  or  bitter  malt 
liquors,  have  a  distinct  influence  in  the  production  of  the 
psychic  secretion  or  appetite  gastric  juice,  and  so  may  favor 
digestion. 

Second  Period. — Knowledge  of  the  effect  upon  the  secretion 
while  the  alcohol  is  in  the  stomach  was  obtained  from  experi- 
ments on  Pawlow  dogs  and  dogs  with  gastric  fistulae,  and  in 
addition  from  a  few  observations  made  upon  patients  with  gas- 
tric fistulae.  A  number  of  studies  were  made  by  Kast  upon  a 
girl  who  had  had  a  portion  of  the  esophagus  removed  and  a 
gastric  fistula  established.  The  work  of  Chittenden  and  Mendel 
was  done  on  dogs  with  gastric  fistulae,  a  regular  meal  being  al- 
lowed by  mouth,  and  measured  quantities  of  alcohol  being  put 
in  through  the  fistula.  From  these  observations  we  learn  that 
the  direct  influence  of  alcoholic  solutions  up  to  about  10  per  cent, 
in  strength  is  practically  none  at  all  upon  either  the  rate  or  the 
character  of  the  gastric  secretion;  while  from  amounts  above 
about  20  per  cent,  secretion  is  distinctly  retarded.  Between 
these  strengths  there  is  a  variable  influence.  There  is  some 
retardation  of  secretion  from  the  malt  beverages  because  of  their 
large  amount  of  extractive  matters,  and  from  the  red  wines  because 
of  their  tannic  acid;  but  the  retardation  in  these  cases  is  not  due 
to  the  alcohol. 

Third  Period. — When  alcohol  is.  injected  into  the  blood  of  a 
dog,  a  flow  of  gastric  juice  results,  and  in  some  of  the  cases  at 
least  some  of  the  alcohol  is  excreted  into  the  stomach.  If 
alcohol  is  placed  in  the  rectum  or  in  any  part  of  the  intestine, 
absorption  is  also  followed  by  a  flow  of  gastric  juice,  the  flow 
being  greater  the  nearer  to  the  stomach  the  alcohol  is  adminis- 
tered. And  when  alcohol  is  placed  in  the  stomach  itself,  a  copious 
flow  of  gastric  juice,  perhaps  two  or  three  times  that  in  control 
dogs,  takes  place  after  all  the  alcohol  has  disappeared  from  the 
stomach  and  passed  into  the  blood.  In  all  these  cases  the  gastric 
juice  contains  hydrochloric  acid  out  of  all  proportion  to  the  amount 
of  pepsin  present.  Radzkowski  has  shown  that  the  pepsin  of 
this  juice  is  merely  that  already  transformed  from  the  pepsinogen 
in  the  glands,  and  that  no  new  pepsin  is  formed  as  the  result  of 


ALCOHOL 


307 


the  absorbed  alcohol,  that  is  to  say,  the  chief  cells  of  the  stomach 
are  stimulated. 

The  secretion  following  administration  by  rectum  or  into 
the  blood  is  much  less  in  amount  than  that  following  stomach 
doses,  but  has  the  same  composition.  The  secretion  after 
absorption  lasts  until  practically  all  the  food  has  passed  the 
pylorus,  and  it  is  probable  that  alcohol  either  stimulates  the  acid- 
secreting  cells  directly,  or  else  causes  the  formation  of  a  hormone, 
which  is  absorbed  into  the  blood  and  stimulates  the  cells.  The 
effects  would  seem  to  be  of  the  same  nature  as  those  from  the 
hormone  known  as  gastric  secretin.  This  increase  in  the  secretion 
of  acid  and  in  the  amount  of  gastric  juice  after  the  absorption 
of  the  alcohol  is  of  practical  importance.  For  when  rectal  feeding 
in  an  irritant  stomach  condition,  such  as  ulcer,  is  adopted  for  the 
purpose  of  saving  the  stomach  from  irritation,  it  is  advisable 
to  omit  alcohol  from  the  enema.  In  old  alcoholics  the  stomach 
usually  is  the  site  of  a  chronic  inflammation. 

Summary. — We  may  sum  up  the  effects  of  alcohol  upon  the 
stomach  and  its  functions,  as  follows: 

1.  In  so  far  as  they  stimulate  the  appetite,  alcoholic  beverages 

induce  a  psychic  secretion  of  gastric  juice. 

2.  While  in  the  stomach,  alcohol  in  10  per  cent,  dilution  has 

little  if  any  effect  upon  the  digestive  chemistry,  the  motor 
activity,  or  the  secretion;  the  wines  and  malt  liquors  tend 
to  retard  secretion  and  the  digestive  chemistry. 

3.  While  it  remains  in  the  stomach,  alcohol  up  to  20  per  cent. 

in  strength  promotes  absorption  of  other  substances. 

4.  After  absorption  from  the  stomach  alcohol  induces  a  copious 

flow  of  gastric  juice  rich  in  hydrochloric  acid  and  poor  in, 
or  devoid  of,  pepsin ;  the  same  qualitative  result  being  ob- 
tained, though  less  in  quantity,  when  alcohol  is  given  by 
rectum  or  injected  directly  into  the  blood. 

5.  Strong  liquors  are  carminative,  but  in  the  empty  stom- 

ach irritate  and  induce  a  secretion  of  thick,  tenacious 
mucus. 

6.  Long-continued  drinking  of  strong  liquors  tends  to  produce 

a  chronic  gastritis. 
Taken  by  mouth,  in  moderation  and  properly  diluted,  alco- 
holic drinks  tend  to  improve  the  appetite  and  to  give  a  feeling  of 
warmth  and  comfort  in  the  stomach,  and  to  promote  the  secre- 
tory and  absorptive  functions.  In  conditions  of  hyperchlor- 
hydria,  hypersecretion,  or  ulcer  of  the  stomach,  they  tend  to  be 
harmful.  Ordinary  amounts  of  even  strong  liquors  taken  at 
meals  are  quickly  brought  down  to  proper  dilution  by  admixture 


308  PHARMACOLOGY  AND  THERAPEUTICS 

with  the  contents  of  the  stomach  and  this  admixture  with  food 
retards  their  absorption  and  their  systemic  activity. 

Intestines.— After  alcohol  in  moderate  quantities  any  amount 
that  may  be  carried  through  the  pylorus  is  probably  too  dilute 
to  have  any  local  effect  in  the  intestine.  After  excessive  drink- 
ing some  of  it  reaches  the  duodenum  and  acts  there  as  an  irritant. 
A  factor  of  influence  upon  the  intestine  may  be  a  delay  in  the 
passage  of  food  from  the  stomach  as  a  result  of  the  induced 
hyperchlorhydria.  (Brandy  has  a  reputation  as  an  intestinal 
astringent,  and  is  used  in  small  amounts  for  diarrhea.) 

Pancreas. — The  amount  of  pancreatic  secretion  is  increased 
even  up  to  five  times  the  normal,  whether  the  alcohol  is  placed 
in  the  stomach,  the  small  intestine,  the  colon,  or  the  rectum. 
It  may  be  that  this  also  is  due  to  increased  formation  of  the 
secretin. 

Of  the  ferments,  experiments  in  vitro  have  demonstrated  that 
alcohol  of  5  per  cent,  strength  is  completely  inhibitory  to  the 
action  of  trypsin  and  amylopsin,  the  proteolytic  and  starch- 
digesting  ferments  of  the  pancreatic  juice;  while  in  any  strength 
up  to  90  per  cent,  it  distinctly  favors  the  action  of  steapsin,  the 
fat-splitting  ferment.  When  added  to  pancreatic  juice,  which  is 
obtained  from  a  fistula,  alcohol  markedly  increases  the  lipolytic 
power  of  the  secretion;  so  it  would  seem  to  have  the  property 
of  changing  the  proferment  into  the  active  ferment,  steapsin. 
After  ordinary  amounts  this  action  upon  the  ferments  does  not 
take  place,  as  little  of  the  alcohol  reaches  the  intestinal  contents. 
After  very  large  amounts  such  an  action  may  influence  the 
intestinal  digestive  process. 

Liver. — From  the  stomach  and  duodenum  the  absorbed 
alcohol  passes  by  the  portal  circulation  directly  to  the  liver. 
Moderate  amounts  are  sufficiently  diluted  by  the  portal  blood. 
Large  amounts,  as  in  excessive  drinking,  surcharge  the  portal 
blood  with  alcohol.  This  attacks  the  hepatic  parenchyma,  as 
shown  by  the  presence  of  albumin  and  epithelial  cylinders  in  the 
bile,  and  swelling  of  the  liver,  with  more  or  less  fatty  degeneration. 
In  other  words,  it  produces  an  acute  hepatitis.  This  usually 
disappears  in  a  few  days  if  no  more  alcohol  is  drunk;  but  a  single 
excessive  dose  does  vastly  more  harm  to  the  liver  than  the  same 
amount  of  liquor  taken  a  little  at  a  time. 

Good-sized  doses  of  liquor,  frequently  repeated  during  many 
years,  tend  to  establish  permanent  changes  in  the  liver — either 
fatty  degeneration  or  connective-tissue  invasion  (cirrhosis),  or 
both. 

It  is  a  well-known  fact  that  the  drinking  of  large  quantities 
of  alcohol  for  years  is  a  regular  prelude  to  the  appearance  of 


ALCOHOL  309 

cirrhosis  of  the  liver.  A  number  of  children  also  who  have  been 
given  beer  or  wine  have  developed  cirrhosis  of  the  liver.  There- 
fore there  is  a  close  relation  between  cirrhosis  and  alcohol.  Yet 
in  animals,  though  the  continued  administration  of  alcohol 
readily  produces  a  fatty  liver,  even  in  starved  dogs  (prevented  by 
sugar — VonNoorden),  yet  almost  all  investigators,  Strassmann, 
Afanassiew,  von  Kahlden,  etc.,  have  been  unable  to  produce 
typical  cirrhosis  even  by  prolonged  administration.  I  have 
reports  of  true  cirrhosis  being  so  produced  in  animals  in  only  two 
cases,  one  in  a  rabbit  and  the  other  in  a  dog.  It  seems,  then, 
that  it  takes  years  of  excessive  alcoholism  before  any  extensive 
connective-tissue  changes  can  be  detected,  and  it  is  quite  prob- 
able that  the  production  of  cirrhosis  of  the  liver  requires  more 
than  alcohol. 

The  Bile. — Alcohol  is  excreted  in  the  bile  only  after  large  doses, 
and  the  amount  excreted  is  quickly  reabsorbed  from  the  intes- 
tine. The  quantity  of  bile,  both  liquid  and  solid  constituents, 
may  be  much  increased  (from  50  to  130  per  cent,  increase  in 
volume,  according  to  Salant,  if  alcohol  is  injected  into  the  stomach 
or  intestines,  but  not  if  it  is  injected  into  the  blood).  Salant's 
experiments  showed  that  when  alcohol  was  given  by  stomach 
the  bile  increased  50  to  365  per  cent.;  when  alcohol  was  placed 
in  the  intestine  the  bile  increased  80  to  140  per  cent.,  and  the 
solid  constituents  were  increased.  This  would  be  the  effect 
expected  coincidentally  with  the  increase  of  pancreatic  secretion 
(Starling)  if  the  alcohol,  as  we  suggested  before,  results  in  in- 
creased production  of  secretin.  It  seems  especially  probable 
that  this  is  the  case,  because  alcohol  itself,  under  ordinary 
circumstances,  does  not  reach  the  intestines  in  strength  sufficient 
to  have  any  effect,  either  direct  or  reflex.  Salant  reported, 
however,  that  alcohol  injected  into  the  blood  caused  a  reduction 
in  the  secretion  of  bile.  In  addition  to  these  effects  excessive 
amounts  may  hasten  the  disappearance  of  glycogen  from  the 
liver,  with  tendency  to  increase  fat  and  lessen  the  oxidative 
processes  of  the  liver,  as  shown  by  the  appearance  of  more 
uric  acid  and  less  urea  in  the  urine,  and  by  an  increase  of  the 
poisonous  symptoms  in  indolic  auto-intoxication.  Several  re- 
searches go  to  show  that  sugars  tend  to  lessen  these  effects. 

Absorption  is  rapid  from  stomach  or  intestines.  It  is  retarded 
by  fats,  as  milk,  cream,  or  oil  emulsions  (Jacoby). 

Nervous  System. — As  alcohol  is  an  ethyl  compound,  C2H5OH 
with  a  close  relation  to  ether,  (C2H5)20,  it  is  not  surprising  to 
find  that  the  alcohol  effect  upon  the  central  nervous  system  is 
the  same  in  kind  as  that  of  ether,  though  modified  by  its  dimin- 
ished volatility  and  slower  action.     It  depresses  first  the  highest 


310  PHARMACOLOGY  AND  THERAPEUTICS 

cerebral  centers  of  all,  the  intellectual  centers,  then  the  lower 
cerebral  centers  (motor,  emotional,  animal),  then  the  cerebellum, 
then  the  spinal  cord,  and  finally  the  vital  centers  of  the  medulla. 
There  is  probably  a  primary  stimulation  from  protoplasmic 
irritation,  but  this  is  momentary,  and  alcohol  cannot  be  con- 
sidered in  any  sense  a  cerebral  stimulant.  It  is  a  true  narcotic, 
and  it  stands  in  the  narcotic  series  between  the  general  anesthe- 
tics, which  are  very  volatile,  very  prompt,  and  transitory  in 
their  action,  and  very  powerful  in  their  effects,  and  the  hypnotics, 
of  which  a  dose  must  be  able  to  maintain  a  mild  degree  of  narcosis 
for  several  hours. 

The  symptoms  of  acute  alcohol  poisoning  or  drunkenness  are 
only  too  familiar.  They  are  readily  explainable  as  the  effects 
of  a  narcotic  drug.  Normally,  our  animal  tendencies  are  under 
the  restraint  of  the  highest  brain  centers — those  through  whose 
activity  are  exerted  will,  self-control,  reasoning  power,  judg- 
ment, etc.  By  these  we  hold  ourselves  to  certain  standards  of 
conduct,  and  keep  in  proper  check  the  more  animal  parts  of  our 
natures.  We  weigh  facts  and  estimate  the  consequences  of  our 
acts:  we  are  thoughtful  of  our  relations  to  others,  and  mind  what 
others  may  think  of  us. 

Under  alcohol  these  highest  faculties  are  depressed,  and  there 
is  a  certain  degree  of  freedom  from  restraint,  i.  e.,  "there  is  a 
breaking  of  the  fetters  which  keep  our  animal  natures  within 
bounds"  (Dubois).  The  result  is  the  failure  of  judgment,  the 
inability  to  appreciate  the  consequences  of  one's  acts,  great  con- 
fidence in  one's  mental  and  physical  powers,  and  a  lack  of  care 
about  the  kind  of  impression  made  upon  one's  neighbors.  Speech 
is  freer,  because  of  less  thinking  before  speaking  and  less  concern 
about  the  best  word  to  say  or  the  best  way  in  which  to  voice 
one's  thoughts.  Confidence  in  one's  powers  extends  to  the 
physical  as  well  as  to  the  mental,  as  seen  in  one's  willingness  or 
anxiety  to  fight  a  man  of  twice  one's  strength,  and  in  the  belief 
of  a  writer  that  he  is  doing  splendid  work,  though  at  a  later 
perusal  he  finds  it  trashy  and  full  of  errors. 

A  great  many  experiments  have  been  performed  to  determine 
the  exact  effect  upon  the  faculties  of  small  quantities  of  alcohol, 
and  while  some  of  them  show  primary  stimulation,  depression 
is  the  rule.  A  study  of  type-setters,  for  example,  has  shown 
that  they  make  more  errors  even  under  very  small  amounts  of 
alcohol;  pianists  strike  more  wrong  notes;  sight  and  hearing  are 
less  keen;  the  sense  of  touch  is  impaired  (as  measured  by  the 
esthesiometer).  Kraepelin's  work  in  this  regard  is  the  most 
striking.  He  found  that  the  perception  of  a  word  or  letter 
flashed  before  the  eye  was  slightly  less  rapid,  but  that  a  motor 


ALCOHOL  311 

response  was  more  rapid;  and  this  might  be  because  of  freedom 
of  the  motor  areas  from  the  inhibition  required  in  judgment. 
In  some  persons  some  of  the  depression  persisted  for  from  twelve 
to  twenty-four  hours.  In  some  there  was  no  depression  at  all, 
even  from  100  c.c.  of  alcohol,  which  would  be  the  amount  in  a 
tumblerful  of  whisky. 

Jacoby  found  that  alcohol  made  a  keener  perception  of  differ- 
ences of  weight,  but  thought  this  due  to  slower  (more  deliberate) 
cerebration.  Some  observers  have  noted  a  brief  period  of  true 
stimulation  of  the  perceptive  faculties  before  the  general  depres- 
sion supervenes.  Many  good  men  have  thought  that  the  quicker 
action  in  response  to  a  stimulus  was  due  to  primary  freeing  of 
the  motor  functions  from  inhibition. 

Alcohol,  then,  is  an  intellectual  depressant,  i.  e.,  a  narcotic, 
and  it  is  a  direct  antagonist  of  caffeine.  Yet  on  some  particular 
occasions,  or  in  special  kinds  of  work,  the  peculiar  narcotic 
effects  of  alcohol  may  actually  favor  better  work,  for  example — 
(a)  Where  nervousness,  or  embarrassment,  or  anxiety  cause  too 
great  inhibition  and  prevent  unembarrassed  thinking,  e.  g.,  one 
who  is  to  speak  in  public  may  increase  his  confidence,  lessen 
his  self-consciousness,  and  set  free  his  thoughts,  so  that  he  can 
speak  without  embarrassment,  (b)  When  the  writer  of  imagina- 
tive or  emotional  literature  or  poetry  is  unable  to  get  himself 
into  the  imaginative  state;  a  dose  of  whisky  may  set  free  his 
imaginative  powers,  so  that  he  can  outline  his  story,  any  errors 
of  grammar  or  construction  being  corrected  later,  (c)  When  a 
musician  is  unable  to  reach  the  emotional  state  necessary  to 
enthuse  his  hearers,  he  may  find  himself  able  to  do  so  after  a 
drink  of  whisky,  for  though  he  may  strike  a  number  of  wrong 
notes,  he  puts  life  into  his  music  and  thrills  his  audience.  These 
are  not  cases  of  intellectual  stimulation,  but  intellectual  depres- 
sion. Though  these  things  are  true  in  particular  instances,  I 
would  caution  against  depending  on  any  such  aid,  for  it  is  impos- 
sible to  predict  the  dose  that  will  just  give  the  desired  assistance. 
Too  much  alcohol  spoils  everything,  for  the  inferiority  of  work 
produced  is  not  realized  by  the  drinker.  Work  requiring  deduc- 
tion and  keenness  of  judgment,  such  as  scientific  writing  or  inves- 
tigation, cannot  be  done  so  well  under  the  influence  of  even 
small  amounts  of  alcohol. 

Sexuality. — From  depression  of  the  cerebrum  the  sexual  de- 
sires are  under  much  less  restraint  than  normal,  and  Havelock 
Ellis  rightly  says:  "It  is  obvious  that  those  who  wish  to  cultivate 
a  strict  chastity  of  thought  and  feeling  would  do  well  to  avoid 
alcohol  altogether,  or  to  use  it  in  its  lightest  forms  and  in  modera- 
tion.''    If  much  alcohol  is  taken,  the  sexual  powers  are  impaired 


312  PHARMACOLOGY  AND   THERAPEUTICS 

from  depression  of  the  spinal  cord,  though  the  animal  desire  may 
still  be  present.  In  chronic  alcoholics  sexuality  is  not  infre- 
quently abolished;  indeed,  atrophy  of  the  testicles  is  frequent. 

Hypnotic  Action. — Other  things  being  equal,  alcohol,  taken 
without  exhilarating  company,  tends  to  promote  drowsiness  and 
sleep.     Hence  the  use  of  beer,  ale,  or  the  hot  toddy  at  bedtime. 

Stupor. — If  much  alcohol  is  taken  in  a  short  time,  the  intoxica- 
tion (exhilaration)  stage  is  followed  by  bodily  inactivity,  mental 
dulness,  and  inattention.  There  is  also  ataxia  from  loss  of 
muscular  sense,  so  that  it  is  difficult  to  button  one's  coat  or  to 
walk  in  a  straight  line  or  to  tell  just  where  one's  legs  are.  The 
gait  is  staggering,  either  because  of  the  ataxia  or  from  cerebellar 
depression,  and  the  speech  is  thick.  During  the  stages  of  intox- 
ication and  stupor  there  is  some  general  anesthesia  from  depres- 
sion of  the  sensory  centers,  so  that  the  alcoholic  may  injure 
himself  without  pain,  as  when  he  burns  his  ringers  with  a  cigar  or 
falls  and  breaks  a  limb.  There  is  also  some  muscular  relaxation 
from  depression  of  the  reflexes,  and  this  accounts  for  the  notice- 
able escape  from  fractures  in  drunken  falls.  As  with  ether,  the 
sensory  centers  are  affected  before  the  motor,  and  there  may  be 
early  impairment  of  feeling  in  the  hands  and  feet,  but  the  loss 
of  muscular  control  may  not  be  noticed  until  the  victim  attempts 
to  walk.  After  this  stage  the  patient  may  pass  into  an  anes- 
thetic, stuporous  sleep,  with  slow  and  perhaps  stertorous  breath- 
ing; and  he  may  even  go  on  to  coma,  collapse,  and  death.  Previ- 
ous to  the  employment  of  ether  and  chloroform  as  anesthetics, 
whisky  in  intoxicating  quantities  was  frequently  administered  as 
a  preliminary  to  major  operations. 

It  is  observed  that  when  liquor  is  taken  without  exhilarating 
surroundings  and  company,  as  by  an  invalid  in  bed,  the  drowsy 
or  quiet  stage  supervenes  without  much  preliminary  exhilaration. 

Therapeutically,  the  only  desired  effect  upon  the  cerebrum  is 
the  narcotic  one  of  quieting  the  nervous  system,  as  in  fevers  or 
emotional  shock  or  insomnia. 

Cerebellum. — In  the  intoxication  there  is  incoordination,  as 
shown  by  staggering  gait,  inability  to  use  the  hands  with  dex- 
terity, and  mixed  or  incoherent  speech.  These  things  may, 
however,  as  mentioned  above,  be  due  to  other  depressions  than 
that  of  the  cerebellum. 

Spinal  Cord. — The  reflexes  are  depressed,  and  the  tone  of 
muscle  and  the  response  to  external  stimuli  are  much  lessened. 
Muscular  relaxation  has  been  spoken  of.  The  bladder  reflex  may 
fail,  so  that  urine  accumulation  distends  the  bladder.  This  may 
go  on  to  a  dangerous  degree,  and  catheterization  become  neces- 
sary.    The  sexual  powers  fail. 


ALCOHOL 


313 


Peripheral  Nerves. — There  is  some  depression  of  the  nerves 
and  nerve-endings,  including  the  nerves  of  muscular  sense, 
though  the  main  factor  in  the  anesthesia  is  central  depression. 
In  the  excessive  and  continued  use  of  alcohol  its  affinity  for  the 
nerves  is  shown  in  the  frequency  with  which  it  produces  a  neu- 
ritis. 

To  sum  up  the  action  of  alcohol  as  a  narcotic  we  might  say 
that  it  produces  practically  the  same  stages  as  ether,  but  that  the 
stages  are  modified  by  the  much  slower  rate  at  which  the  narcosis 
is  produced;  and  that  as  alcohol  is  usually  taken  by  stomach, 
rather  than  by  inhalation,  any  irritant  effects  manifest  them- 
selves upon  the  stomach  and  liver  instead  of  upon  the  nose, 
throat,  and  bronchi. 

The  stages  of  alcohol  narcosis  are : 

1.  Stage  of  blunted  perceptive  and  intellectual  faculties. 

2.  Intoxication — a  much  prolonged  stage. 

3.  Stupor — general  dulness  and  inattention  leading  to  stupor- 
ous sleep. 

4.  Coma  (serious),  leading  to  collapse  and  death. 

The  apparent  stimulating  effects  of  alcohol  are  dependent 
essentially  upon  the  following  factors: 

1.  The  local  irritation — this  results  in  true  reflex  stimulation 
of  the  circulation,  but  of  only  short  duration.  The  less  the  dilu- 
tion, the  greater  is  the  reflex  effect. 

2.  The  feeling  of  warmth — due  to  general  dilatation  of  the 
skin  vessels. 

3.  The  early  narcotic  effect  of  depression  of  the  higher  centers, 
with  freedom  of  the  imaginative  and  emotional,  and  increase  of 
confidence  in  one's  physical  and  mental  powers. 

4.  The  food  value — which  is  a  striking  factor  in  debility  and 
exhaustion. 

5.  In  company,  the  effect  of  increased  sociability  and  exhila- 
rating environment. 

Food  Value. — A  food  may  be  defined  as  a  substance  whose 
dominant  property  in  the  body  is  to  build  up  the  tissues  or  to 
yield  energy.  Protein  is  our  reliance  for  the  building  or  recon- 
struction of  tissue;  carbohydrates  and  fats  are  restricted  to  fur- 
nishing energy.  It  is  evident,  from  its  chemical  constitution, 
that  alcohol  has  no  power  to  build  tissue.  We  might  inquire, 
then,  into  its  value  in  the  production  of  energy. 

To  What  Extent  Can  Alcohol  be  Oxidized  in  the  Body? — God- 
dard  administered  16  gm.  of  absolute  alcohol,  properly  diluted, 
to  a  fasting  dog  weighing  12.4  kilos  (about  25  pounds),  and  found 
that  all  the  alcohol  had  disappeared  in  five  and  one-half  hours, 
and  that  only  about  5  per  cent,  of  it  had  been  recovered,  some 


314  PHARMACOLOGY   AND   THERAPEUTICS 

in  the  breath  and  some  in  the  urine,  i.  e.,  95  per  cent,  had  been 
completely  oxidized.  If  humans  oxidize  alcohol  at  the  same  rate, 
a  man  of  160  pounds  could  dispose  of — i.  e.,  burn  up  and  utilize 
for  energy — 6  ounces  of  whisky  given  at  one  dose — about  three- 
fourths  of  a  tumblerful,  or  enough  to  produce  drunkenness.  To 
test  this  Atwater  and  Benedict  treated  healthy  men  with  six 
i-ounce  doses  given  with  food  at  intervals  during  the  day.  It 
was  completely  oxidized,  except  for  the  small  amount  of  1.9  per 
cent,  that  was  recovered  from  the  breath  and  urine.  Alcohol 
in  any  ordinary  amounts  is,  therefore,  practically  completely 
burned  up  by  the  body.  In  Goddard's  experiments  larger 
amounts  than  mentioned  above  resulted  in  the  appearance  in 
the  breath  and  urine  of  aldehyde  and  other  incompletely  oxidized 
products  of  alcohol. 

Can  Alcohol  Directly  Replace  Fats  in  the  Food? — Atwater  and 
Benedict  placed  a  man  on  a  fixed  diet  of  mixed  character.  Dur- 
ing thirteen  days  of  resting  he  increased  in  weight  an  average  of 
33.7  gm.  daily,  i.  e.,  stored  up  that  much  surplus.  When  for 
ten  days  72  gm.  alcohol,  as  in  6  ounces  of  whisky  or  a  quart  of 
claret,  was  given  each  day,  and  its  equivalent  in  fat  deducted 
from  the  daily  dietary,  the  average  gain  was  34.1  gm.  daily.  It 
was  not  alcohol  that  was  stored  up,  but  fat,  the  alcohol  being 
burned  up  first  to  supply  the  energy,  and  a  corresponding  amount 
of  fat  being  spared  to  be  stored  up.  There  was  no  increase  in 
the  intake  of  oxygen  or  the  output  of  CO 2  other  than  that 
normally  following  the  ingestion  of  food. 

These  same  experimenters,  Atwater  and  Benedict,  also 
studied  the  metabolism  of  a  man  who  was  fed  for  alternating 
periods  of  five  days  on  a  definite  mixed  diet  and  on  the  same  diet, 
but  with  72  gm.  of  alcohol  replacing  an  isocaloric  amount  of  fat 
in  the  daily  allowance.  During  the  first  two  periods  of  five  days 
the  man  was  at  rest,  and  during  two  other  five-day  periods  he 
was  at  hard  work.  They  found  that,  both  during  the  rest 
periods  and  the  hard-work  periods,  the  total  metabolism  was 
practically  the  same  on  the  alcohol  dietary  as  on  that  containing 
fat.  Therefore  alcohol  supplied  the  energy  for  rest  or  for  work 
just  as  well  as  fat  did,  and  prevented  drawing  upon  the  tissues. 

We  might  refer  also  to  the  experiments  of  Hellsten  and  of 
Schnyder  and  Dubois,  and  of  the  German  government  (see 
below),  which  established  the  energy-producing  value  of  alcohol 
when  the  regular  food-supply  was  deficient.  The  experiments 
of  Rosemann  (1 901)  on  himself  over  a  period  of  thirty-seven  days, 
and  of  Neumann  (1901)  on  dogs  in  two  periods  of  twenty-five 
and  thirty-six  days,  give  also  some  exact  data  as  to  the  ability  of 
alcohol  to  prevent  tissue  waste  and  to  replace  fat  in  the  dietary. 


ALCOHOL  315 

One  of  Neumann's  experiments  was  as  follows:  For  five  days  he 
kept  dogs  in  nitrogen  equilibrium  (that  is,  on  a  mixed  diet  whose 
daily  nitrogen  was  the  same  in  amount  as  the  daily  excretion  of 
N).  He  then  for  four  days  gave  the  same  diet,  but  with  half  its 
fat  omitted;  the  nitrogen  excretion  increased,  showing  that  there 
was  more  protein  destruction,  i.  e.,  the  proteins  were  being  drawn 
upon  to  supply  the  energy  that  the  fat  had  supplied.  Then 
alcohol,  in  amount  chemically  equivalent  to  the  omitted  fat, 
was  added  to  the  food,  and  the  nitrogen  equilibrium  again  became 
established.  Therefore  alcohol  was  able  to  spare  the  proteins 
in  the  same  way  as  the  fat.  But  Neumann  went  further,  and 
not  only  gave  the  alcohol,  but  also  replaced  the  omitted  fat,  and 
the  nitrogen  excreted  became  less  than  that  ingested,  i.  e.,  there 
was  less  protein  destruction  than  with  either  alcohol  or  fat  alone, 
and  protein  was  being  stored  up,  so  that  alcohol  performed  the 
function  of  fat  in  sparing  protein  even  when  the  fat  in  the  food 
was  sufficient.  Lastly,  Neumann  omitted  both  the  fat  and  the 
alcohol,  and  the  nitrogen  excretion  again  greatly  exceeded  that 
taken  in  with  the  food,  that  is,  there  was  excessive  protein  de- 
struction. We  might  sum  up  the  teachings  of  these  experiments 
as  follows :  When  fat  in  the  food  is  deficient,  alcohol  can  entirely 
compensate  for  the  deficiency,  at  least  for  a  short  period;  it  yields 
the  energy  that  fat  would  yield,  and  so  spares  protein  and  prevents 
tissue  waste.  When  alcohol  and  fat  are  administered  together  in 
quantities  above  the  needs  of  the  body,  the  alcohol  is  the  more  easily 
utilized  to  supply  energy,  so  that  the  fat  is  spared  and  stored  up  in 
the  body. 

(In  metabolism  experiments  with  alcohol  it  has  been  found 
that  there  is  usually  a  loss  in  protein  for  the  first  three  or  four 
days  until  tolerance  is  established;  but  if  the  alcohol  is  begun  in 
very  small  doses,  the  primary  protein  destruction  does  not  occur; 
and  in  those  accustomed  to  alcohol,  even  larger  quantities  of 
alcoholic  drinks  result  in  no  primary  nitrogen  loss,  even  in  fever. 
— Ott.) 

Can  Alcohol  Directly  Replace  Carbohydrates  in  the  Food? — 
To  test  this,  Atwater  and  Benedict  examined  excreta  of  a  man  at 
rest  during  five-day  periods.  During  the  first  period  he  was  on  a 
fixed  diet,  without  sugar,  representing  2290  absorbable  calories. 
He  gained  very  slightly  in  weight,  the  daily  calories  of  metabolism 
being  2176,  and  the  calories  of  retention  being  77.  During  the 
second  period  he  took  the  same  diet  plus  72  gm.  of  alcohol  (500 
calories),  and  gained  more  in  weight;  the  calories  of  metabolism 
being  2258  and  those  of  retention  589.  During  the  third  period 
he  took  the  same  diet  with  the  exclusion  of  the  alcohol,  and  the 
substitution  therefor  of   130  gm.  of  sugar  (515  calories);  the 


316 


PHARMACOLOGY  AND  THERAPEUTICS 


calories  of  metabolism  being  2272  and  those  of  retention  562, 
practically  the  same  as  with  the  alcohol.  There  was  no  essential 
difference  in  the  intake  of  oxygen  or  output  of  carbon  dioxide, 
except  that  associated  with  the  taking  of  any  food. 


Absorbable 
Calories 


Calories  of 
Metabolism 


Calories  of 

Retention  in 

Weight 


Fixed  diet 

Fixed  diet  +     72  gm.  alcohol 
Fixed  diet  +  130  gm.  sugar  . 


2290 

2290  +  500 

2290  +  515 


2176 
2258 
2272 


77 
589 
562 


Rosenfeld  (1900),  in  an  eleven-day  experiment  with  a  nitrogen 
equilibrium  diet,  found  that  120  gm.  of  alcohol  caused  a  nitrogen 
saving  of  17  per  cent.,  and  that  a  corresponding  sparing  of 
nitrogen  occurred  from  equivalent  amounts  of  cane-sugar.  From 
these  data  we  may  conclude  that  alcohol  in  moderate  quantities 
given  with  a  mixed  diet  can  replace  equivalent  amounts  of  carbo- 
hydrates in  the  food,  at  least  for  a  short  period. 

The  caloric  value  of  alcohol  is  7.1  calories  per  gram — i.  e., 
one  gram  of  alcohol  is  equivalent  in  energy-producing  power  to 
1.75  grams  of  carbohydrate,  or  0.77  gram  of  fat. 

The  beer-drinkers'  adipose  is  well  known.  In  the  malt 
liquors  there  is  much  nutritive  albuminous  and  carbohydrate 
material  in  addition  to  the  alcohol.  A  Liter  of  beer  containing 
5  per  cent,  by  volume  of  alcohol  would  contain  50  c.c.  (40  gm.) 
of  alcohol,  representing  284  calories,  and  extractive  matter 
representing  from  200  to  275  calories,  according  to  its  "body." 
Hence  a  liter  of  beer  may  furnish  500  calories,  or  as  much  as  one- 
sixth  of  the  necessary  food  requirements  of  a  man  at  work. 

An  interesting  theory,  held  by  some  biologists,  is  that  the 
pancreas,  by  means  of  a  ferment,  converts  carbohydrates  into 
alcohol,  which  is  then  oxidized  in  the  tissues  to  produce  energy. 
Fat  is  deposited  in  the  tissues  as  the  result  of  an  intracellular 
synthesis  of  alcohol  and  a  fatty  acid. 

Muscle,  Power,  and  Endurance. — Lee  and  Salant  found  that 
in  frogs,  while  weak  alcohol  has  little  effect  on  striated  muscle, 
10  per  cent,  alcohol  is  a  direct  stimulant.  In  26  experiments  on 
the  contraction  of  a  curarized  frog's  gastrocnemius  the  average 
increase  in  the  number  of  contractions  in  the  alcoholized  frog 
was  59.5  per  cent.,  and  the  average  increase  of  total  work  done 
by  the  muscle  was  40.4  per  cent.  Their  conclusion  was  that 
alcohol  in  moderate  quantities  results  in  quicker  contraction  and 
quicker  relaxation  of  the  muscle,  with  a  larger  number  of  con- 


ALCOHOL 


317 


tractions,  increased  amount  of  work  in  a  given  time,  and  delay 
of  fatigue.  In  these  cases,  of  course,  there  was  no  supply  of 
nutritive  material  and  the  alcohol  may  have  served  as  food. 

Human  ergographic  and  dynamometric  experiments  indicate 
that  small  quantities  increase  the  power  for  muscular  work  for 
a  short  time,  but  that  fatigue  sets  in  more  early. 

Hellsten  (1904)  showed  that  10  gm.  of  alcohol  given  to  a  non- 
drinker  increased  the  muscular  power  for  the  first  half-hour  up  to 
9  per  cent.,  the  best  work  being  done  during  the  second  period  of 
fifteen  minutes;  in  the  third  period  of  fifteen  minutes  the  mus- 
cular power  decreased  to  6  per  cent,  below  normal.  After  mod- 
erate fatigue  the  primary  increase  after  alcohol  was  more  notice- 
able. From  his  experiments  he  concluded  that  there  was  some 
primary  stimulation  either  of  the  motor  centers  or  muscle,  and 
that  in  fatigue,  or  when  nutritive  material  was  lacking,  the  effect 
of  the  alcohol  as  food  enhanced  the  stimulation.  The  subse- 
quent decrease  in  muscular  power  is  essentially  due  to  the  depres- 
sion of  the  motor  centers  of  brain  and  cord. 

Schnyder  and  Dubois  (1903)  compared  alcohol  with  tropon 
(a  protein  food).  From  over  400  ergograph  experiments  they 
concluded  that  alcohol  in  small  quantities  has  a  favorable  action 
on  muscular  power  when  it  is  taken  by  a  fasting  person  who  has 
to  some  degree  exhausted  his  reserves  by  active  work.  But  that 
because  of  the  central  depressant  effect  the  increase  in  muscular 
power  is  below  that  from  an  ordinary  food  substance  of  the  same 
caloric  value;  and  that,  if  the  individual  has  already  an  adequate 
food-supply,  the  late  depression  of  muscular  power  may  be  the 
only  manifestation  of  the  alcohol. 

It  is  evident  from  such  experiments  that  any  good  effects  on 
muscle  and  work  depend  not  on  stimulation,  but  on  nutrition. 

Endurance. — Tests  with  soldiers  over  a  number  of  days  have 
shown  that,  in  a  regiment  on  the  march,  provided  that  all  were 
well  fed,  those  companies  which  received  no  alcohol  during  the 
day  were  able  to  march  further  or  were  in  better  condition  at  the 
end  of  the  day  than  the  companies  which  received  alcohol.  If 
they  were  underfed,  those  receiving  alcohol  in  the  ration  could 
endure  the  most.  As  the  result  of  extensive  experiments  of  this 
kind  made  by  Leistenstorfer,  the  German  Government  decided 
to  replace  alcoholic  stimulants  with  sugar  or  sweetened  chocolate. 

Zuntz  and  Schumberg  made  a  study  on  the  temperature  of 
marching  soldiers,  and  found  that  while  normally  they  could 
carry  an  average  load  of  22  kilograms  and  march  15  to  20  kilo- 
meters without  noticeable  rise  in  body-temperature,  yet  from  the 
same  work,  after  a  drinking-bout,  the  temperature  rose  to  from 
102.70  F.  (39.30  C.)  to  1050  F.  (40.50  C).     Parkes  speaks  of  a 


318  PHARMACOLOGY  AND   THERAPEUTICS 

march  of  400  miles  across  the  Egyptian  desert  by  an  English 
army  in  1800.  The  fatigue  of  the  march  was  probably  never 
exceeded  by  any  army.  No  spirits  were  served,  and  the  men 
kept  in  strikingly  good  health.  One  day  some  of  the  soldiers 
obtained  some  date  brandy  and  became  intoxicated,  and  during 
the  following  three  months  a  considerable  number  of  these  men 
were  in  hospital. 

Summary. — We  might  state  our  conclusions  from  the  scien- 
tific evidence  as  follows: 

Alcohol  cannot  build  up  tissue,  but  it  can  spare  or  replace 
fats  and  carbohydrates  in  the  food, 'and  can  prevent  excessive 
protein  destruction  (tissue  waste)  for  a  time.  It  may,  therefore, 
serve  as  a  useful  food  in  some  conditions  of  great  exhaustion  or 
waste,  where  the  tissues  would  otherwise  be  broken  down  to 
furnish  the  energy  to  maintain  life.  But  in  any  case  alcohol 
cannot  be  a  profitable  food  for  any  great  length  of  time,  because 
of  its  central  nervous  effects,  and  because  it  causes  too  marked 
wear  and  tear  on  the  body  structures.  It  is  probable  that  in 
most  conditions  any  sugar  will  be  a  better  food. 

The  use  of  alcohol  as  a  source  of  energy  to  the  body  may  be 
aptly  compared  with  the  employment  of  sea-water  in  a  boiler 
to  produce  steam.  It  will  produce  the  steam  and  run  the  engine 
in  an  emergency,  but  if  its  use  is  continued,  will  eventually 
cause  the  engine's  destruction. 

Alcohol,  therefore,  under  special  circumstances,  may  have  a 
food  value;  but  it  should  not  be  classed  among  the  foods,  because 
its  property  of  yielding  energy  is  not  its  dominant  property,  and 
is  overshadowed  by  important  pharmacologic  actions,  viz. : 

1.  Its  irritant  local  action. 

2.  Its  destructive  action  upon  the  body  tissues. 

3.  Its  narcotic  action. 

4.  Its  proneness  to  result  in  the  formation  of  a  vicious  habit. 
All  these  dominant  properties  place  alcohol  among  the  power- 
ful drugs  and  poisons,  rather  than  among  foods. 

As  a  matter  of  fact,  nowadays,  alcohol  to  sustain  one  during 
work  is  very  little  employed.  Persons  who  are  to  undergo  severe 
mental  or  physical  exertion  prefer  to  refrain  from  alcohol  before 
or  during  the  effort,  for  they  find  that  without  the  liquor  they 
can  do  their  work  better,  and  keep  at  it  with  a  clear  mind  for  a 
longer  time.  If  a  strain  is  prolonged,  however,  and  keenness  of 
intellect  is  not  the  first  consideration,  as  in  the  case  of  a  mother 
worn  out  with  anxiety  about  a  sick  child,  a  little  alcohol  may  have 
a  valuable  sustaining  power,  for  it  supplies  readily  absorbable 
food  that  requires  no  gastric  secretion  for  its  digestion;  and,  in 


ALCOHOL  319 

addition,  through  its  narcotic  effect,  tends  to  lessen  excitability 
and  the  wear  and  tear  upon  the  nervous  system. 

After,  but  not  during,  a  severe  exertion  or  strain  an  alcoholic 
drink  may  be  of  benefit  for  three  reasons:  (1)  Its  food  value; 
(2)  its  immediate  reflex  exhilarating  effect,  and  (3)  its  subse- 
quent narcotic  or  sedative  effect,  which  promotes  the  feeling  of 
relaxation  and  comfort  and  rest. 

Circulation. — Before  Absorption. — On  the  ingestion  of  strong 
alcoholic  liquors  there  is  an  immediate  rise  in  arterial  pressure, 
the  rate  of  the  beat  usually  remaining  about  the  same.  But 
though  the  action  lasts  only  a  few  moments,  it  is  an  invaluable 
one  in  mild  functional  forms  of  collapse  (feelings  of  faintness, 
fainting,  etc.).  From  experiments  with  unanesthetized  animals 
Brooks  reports  that  while  alcohol  placed  in  the  mouth  gave  a 
striking  reflex  rise  of  arterial  pressure,  which  returned  to  normal 
in  five  or  ten  minutes,  and  was  followed  by  a  slow  fall  in  pressure, 
alcohol  placed  in  the  stomach  through  a  gastric  fistula  gave  no 
rise  in  pressure,  even  in  strengths  up  to  50  and  60  per  cent.  It 
is  probable,  therefore,  that  the  reflex  comes  from  the  mouth. 

After  Absorption. — The  effect  of  alcohol  upon  the  circulation 
after  absorption  has  been  the  subject  of  much  controversy. 
Until  a  few  years  ago  it  was  in  almost  universal  use  as  a  powerful 
heart  stimulant;  while  in  recent  years  the  pendulum  has  swung 
in  the  other  direction,  and  comparatively  little  alcohol  is  pre- 
scribed. It  might  be  in  order,  therefore,  to  review  the  pharma- 
cologic data  bearing  on  this  point,  remembering  that  studies  in 
animals  anesthetized  by  ether  or  chloroform  tend  to  be  mis- 
leading, because  of  the  similarity  of  the  alcohol  action  to  that  of 
these  anesthetics. 

At  the  Massachusetts  General  Hospital,  Richard  Cabot  made 
1 105  observations  in  58  cases  of  typhoid  fever,  pneumonia,  heart 
disease,  cirrhosis  of  the  liver,  pulmonary  and  peritoneal  tuber- 
culosis, and  other  conditions,  to  determine  the  clinical  effect  on 
arterial  pressure.  For  the  first  twenty-four  hours  he  gave  £ 
ounce  (15  c.c.)  of  whisky,  well  diluted,  every  four  hours,  and 
during  the  second  twenty-four  hours  1  ounce  (30  c.c.)  every 
four  hours.  Observations  were  taken  at  first  at  ^--hour  intervals, 
then  every  two  hours,  and  finally  every  four  hours.  In  no  case 
did  either  the  maximum  or  minimum  arterial  pressure  show  any 
change  that  could  be  attributed  to  the  alcohol.  This  is  valuable 
data,  but  its  importance  must  not  be  exaggerated,  for,  as  we  have 
learned  under  Digitalis,  arterial  pressure,  owing  to  man's  sensi- 
tive mechanisms  for  regulating  it,  cannot  be  taken  as  a  measure 
of  the  improvement  of  the  circulation  brought  about  by  a  drug. 

The  laboratory  data  may  be  summed  up  as  follows : 


320  PHARMACOLOGY  AND  THERAPEUTICS 

On  the  Heart. — In  perfusing  the  coronaries  of  a  dog's 
isolated  heart  Langendorff  and  Loeb,  independently,  found  that 
an  addition  to  the  perfusion  fluid  of  y^-g-  to  ^  (Langendorff 
used  o.oi  to  o.i  per  cent.;  Loeb  used  0.13  to  0.3  per  cent.)  of  1 
per  cent,  of  alcohol  resulted  in  increased  strength  of  systole  and 
increased  output  of  the  heart.  This  was  not  marked,  as  it  would 
be  from  strophanthin  or  adrenaline,  but  was  enough  to  measure. 
If,  however,  more  than  1  per  cent,  of  alcohol  was  added  to  the 
perfusion  fluid,  there  was  muscular  depression  with  dilatation 
of  the  heart  and  stoppage  in  diastole.  Wood  and  Hoyt  (1905), 
working  with  a  reptile  heart,  and  with  a  nutritive  perfusion 
fluid  to  eliminate  any  nutritive  effect  of  alcohol,  obtained  prac- 
tically the  same  results.  With  strengths  of  0.25  and  0.5  per  cent., 
the  output  from  the  heart  was  persistently  increased.  With 
strengths  of  0.5  to  1  per  cent,  there  was  a  primary  increase, 
followed  in  a  few  minutes  by  a  distinct  decrease  in  the  output. 
With  strengths  of  over  1  per  cent,  and  sometimes  with  strengths 
of  less  than  this  the  muscular  activity  decreased  at  once.  On 
changing  from  an  alcoholic  to  a  non-alcoholic  perfusion  fluid, 
the  effect  ceased  quite  promptly,  the  muscle  readily  giving  up  its 
alcohol.  There  were  no  destructive  changes  in  the  heart  muscle 
or  permanent  impairment  of  its  tone.  An  animal  has  recovered 
after  the  alcohol  in  its  blood  had  risen  to  0.6  per  cent. 

These  experiments  indicate  that  alcohol  in  small  quantity 
in  the  blood  stimulates  the  heart  muscle  and  causes  a  slightly 
increased  output,  while  alcohol  in  large  quantities  is  depressing. 

As  the  amount  of  blood  in  the  body  averages  -^  the  body 
weight  (Starling),  a  man  of  150  pounds  would  have  7-^  pounds 
of  blood;  and  to  make  0.5  per  cent,  solution  of  this  would  require 
the  direct  mixing  of  it  with  -f  ounce  pure  alcohol,  or  about  i^ 
ounces  of  whisky.  Through  the  stomach  it  would  require  much 
more  alcohol  than  this,  for  while  the  alcohol  is  being  absorbed 
from  the  stomach,  some  of  it  is  escaping  from  the  blood  and  being 
used  up  by  the  tissues.  Therefore  more  whisky  than  the  above 
amount  would  have  to  be  taken  to  make  a  harmful  effect  upon 
the  normal  heart.  Schweisheimer  has  found  the  alcohol  in  the 
blood  of  a  drunken  man  in  amounts  as  high  as  2.26  per  cent. 

In  fatigue  and  debility  experiments  Locke  and  others  have 
shown  that  0.5  per  cent,  of  dextrose  in  the  blood  will  resuscitate 
a  partly  exhausted  heart;  and,  as  we  have  seen,  many  experiments 
show  that  alcohol  can  to  some  extent  replace  dextrose  as  a  nutri- 
ent. Therefore  it  may  be  assumed  that  when  other  food  material 
is  not  available,  alcohol  can  serve  as  a  nutritive  to  cardiac  muscle 
as  well  as  to  skeletal  muscle. 

Alcohol,   then,   in  moderate  quantities,   acts   slightly  as   a 


ALCOHOL  321 

direct  stimulant  to  the  heart  muscle,  and  also  probably  in  de- 
bilitated persons  as  energy-supplying  food  for  the  heart.  In 
nervous,  restless,  excited  persons  it  may  result  in  a  secondary 
quieting  of  the  heart  through  its  narcotic  effect. 

The  rate  of  the  heart  is  quickened,  at  first  because  of  the  reflex 
effect  from  the  mouth,  later  possibly  because  of  direct  depression 
of  the  vagus  center  or  of  direct  muscular  stimulation. 

Arteries. — In  perfusion  of  an  isolated  viscus  there  is  no  effect 
unless  the  alcohol  percentage  is  above  that  compatible  with  life. 

Arterial  Pressure. — From  ordinary  amounts  there  is  regu- 
larly no  change  in  pressure,  but  when  intoxicating  doses  are 
given,  there  is  a  slow  and  very  gradual  moderate  fall.  The 
arterioles  are  dilated,  as  shown  by  the  increase  in  volume  of  an 
organ  placed  in  an  oncometer.  This  is  due  to  depression  of  the 
vasoconstrictor  center,  for  in  an  animal  with  spinal  cord  severed 
to  cut  off  central  control  of  the  splanchnic  arteries  the  pressure 
tends  to  rise. 

Brooks,  experimenting  with  unanesthetized  animals,  found 
that,  about  fifteen  minutes  after  alcohol  was  placed  in  the 
stomach  through  a  gastric  fistula,  there  resulted  a  very  gradual 
fall  in  pressure  that  lasted  about  an  hour.  When  the  alcohol 
was  given  intravenously  in  small  amounts,  there  was  either  no 
change  in  pressure,  or  a  slight  fall,  followed  by  rapid  recovery; 
from  large  amounts  there  was  a  continuous  and  gradual  fall, 
with  decreased  amplitude  of  the  pulse  and  increased  rate. 

Though,  ordinarily,  there  is  no  rise  in  arterial  pressure,  the 
rate  of  flow,  as  measured  by  the  stromuhr,  is  increased  (Wood 
and  Hoy t) .  This  means  a  greater  supply  of  blood  to  the  organs, 
an  effect  not  appreciated  from  blood-pressure  experiments. 

The  cutaneous  arterioles  are  regularly  dilated,  even  from 
therapeutic  doses,  so  that  the  skin  is  flushed,  and  there  is  a 
feeling  of  warmth  and  comfort,  and  there  is  a  tendency  to 
sweating.  In  susceptible  persons  even  a  teaspoonful  of  a  strongly 
alcoholic  tincture  is  enough  to  flush  the  face  or  even  to  give  a 
feeling  of  light-headedness. 

To  sum  up,  the  effects  upon  the  circulation  are: 

1.  Before  Absorption. — Reflex  stimulation  and  rise  in  arterial 
pressure  from  local  irritation  of  the  mouth  or  throat.  This  is 
the  main  action  upon  the  circulation. 

2.  After  Absorption. — (a)  From  moderate  amounts,  slight 
direct  stimulation  of  the  heart  muscle  and  dilatation  of  the  skin 
vessels; from  large  amounts,  direct  depression  of  the  heart  muscle. 
(b)  Depression  of  vasoconstrictor  center  and  perhaps  of  vagus 
center,     (c)  Acceleration  of  blood-flow  without  rise  in  blood- 


322  PHARMACOLOGY  AND  THERAPEUTICS 

pressure,  (d)  Dilatation  of  the  skin  vessels,  (e)  In  debility- 
it  may  serve  as  a  source  of  energy  for  the  heart. 

Respiration. — Willmann  gave  a  rabbit  a  little  oil  of  mustard 
in  10  c.c.  of  saline  by  mouth.  There  was  no  effect  on  respiration, 
though  the  stomach  mucosa  was  very  red  and  irritated.  He 
gave  a  rabbit  alcohol,  and  though  the  stomach  did  not  show 
any  irritation  and  did  not  differ  from  that  of  a  control,  there  was 
great  increase  in  the  depth  and  frequency  of  respiration.  He 
believed,  therefore,  that  the  stimulus  was  not  from  irritation  of 
the  stomach.       , 

Experiments  were  also  made  on  human  beings  by  Binz  and 
his  pupils.  In  one  case,  for  example,  75  centiliters  of  old  sherry 
was  given  at  8.25  A.  m.  The  respiration  rose  from  3  to  4.25 
liters  of  air  per  minute,  reached  5  liters  at  10.30,  then  fell  again, 
but  was  4  liters  at  11.30.  The  student  was  somnolent  during  this 
time,  as  he  was  unaccustomed  to  wine. 

The  Effect  on  Respiration  in  Fatigue. — A  boy  of  fifteen  years, 
weighing  45  kilos,  was  given  20  c.c.  alcohol  plus  12  gm.  sugar,  a 
little  lemon-juice,  and  80  c.c.  water.  How  much  effect  the  sugar 
would  have  was  not  determined.     The  effects  were  as  follows: 

(a)  When  not  fatigued  — in  10  minutes  after  alcohol — air  resp.  =  +  6.39  per  cent. 

40         "  "  "  "      "      =+   2.74   "      " 

60         "  "  "  "      "      =-    7-77    "      " 

(b)  When  slightly  tired— in  10         "  "  "  "      "      =+12.00   "      " 

30  "  "  "      -     =+11.20   "      " 

40         "  "  "  "      "     =+  4.25    "      H 

(c)  When  very  tired      — in  10  "      "     =+26.80 

30         "  "  "  "      "      =+33-i9    "      " 

40         "  "  "  "      "      =+52.34    "      " 

Weissenfeld  tested  74  cases,  and  Wendelstadt,  55.  These 
men,  and  Zuntz  and  Bardez,  von  Taksch,  and  Geppert  obtained 
uniformly  similar  results. 

Therefore  alcohol  during  fasting  or  fatigue  causes  a  con- 
siderable increase  in  respiration,  the  same  increase  occurring 
during  sleep.  "The  increase  is  apparently  central,  and  is 
greatest  from  wines  because  of  their  ethers"  (Binz). 

Loewy's  experiments  seem  to  show  that  there  is  no  increase 
in  the  sensitiveness  of  the  center  to  carbon  dioxide,  and  the  exact 
site  of  action  of  alcohol  in  increasing  respiration  is  not  known. 
In  late  stages  of  poisoning  the  respiratory  center  becomes 
greatly  depressed. 

Temperature.— Through  the  dilatation  of  the  skin  vessels 
and  the  sweating,  alcohol  increases  the  dissipation  of  heat,  and 
so  tends  to  lower  the  temperature.  As  the  skin  is  the  seat  of 
the  important  temperature  nerve-endings,  the  great  amount  of 


ALCOHOL  323 

blood  in  the  skin  vessels  gives  a  feeling  of  warmth.  It  also  makes 
one  more  susceptible  to  changes  in  the  surrounding  temperature, 
so  that  though  on  a  cold  day,  immediately  after  a  drink  of  whisky, 
one  may  feel  warm,  it  is  a  spurious  warmth;  for  the  dilatation 
of  the  skin  vessels  which  makes  one  feel  warm  results  in  more 
blood  being  brought  to  the  surface  to  be  cooled,  so  that  the  body 
temperature  falls.  In  other  words,  there  is  excessive  heat  dis- 
sipation. In  arctic  explorations  the  men  are  never  allowed 
liquor  at  all,  because  it  makes  them  more  susceptible  to  cold. 
Whisky  is  often  effectively  employed  to  prevent  a  cold  after 
exposure,  on  the  theory  that  dilatation  of  the  cutaneous  arte- 
rioles will  counteract  the  results  of  chilling  of  the  surface.  In 
very  hot,  humid  weather  alcohol  predisposes  to  heat-stroke, 
but  this  is  probably  due  to  its  effect  on  the  central  nervous 
system. 

Heat-production  shows  an  increase  during  the  stage  of 
intoxication  owing  to  the  increased  activity,  and  a  decrease 
during  the  stage  of  stupor,  owing  to  depression  of  activity. 
Alcohol  in  medicinal  amounts  is  regularly  a  mild  antipyretic. 

It  might  be  thought  that  the  oxidation  of  alcohol  would 
result  in  excessive  heat-production,  but,  as  we  have  learned, 
alcohol,  in  being  oxidized,  does  not  increase  the  normal  oxidation, 
but  merely  replaces  a  part  of  the  normal  oxidizable  material,  i.  e., 
food.  It  induces  no  change  in  the  02  inspired,  or  the  C02  given 
off,  and  no  change  in  heat-production. 

Elimination. — Von  Noorden  states  that  1.5  to  6  per  cent,  is 
eliminated  in  the  breath,  1  to  2  per  cent,  in  the  urine,  and  traces 
in  the  sweat.  As  we  have  seen  above,  from  6  one-ounce  doses 
of  whisky  a  day  as  little  as  1.9  per  cent,  may  escape  combustion 
(Atwater  and  Benedict),  and  if  quantities  above  6  ounces  are 
taken,  aldehyde  and  other  incompletely  oxidized  bodies  may 
appear  in  the  breath  and  urine  (Goddard).  Alcohol  never 
appears  in  the  feces;  nor  from  any  beverage  amount  does  it 
appear  in  the  milk  of  nursing  mothers  or  affect  its  quality  (Rose- 
mann,  Klinemann).  It  is  said  to  pass  freely  into  the  fetal  cir- 
culation if  taken  by  a  pregnant  woman.  The  odorous  principles 
of  wines  and  distilled  liquors  are  excreted  by  the  lungs,  and  tend 
to  pervade  the  breath  in  somewhat  modified  form. 

Uterus. — In  experiments  with  pregnant  rabbits  alcohol  in 
intoxicating  amounts  frequently  caused  abortion. 

Kidneys. — After  excessive  drinking  there  is  regularly  an 
increase  in  the  excretion  of  urine.  Tliis  may  be  the  result  of 
irritation  of  the  kidney  parenchyma,  or  of  the  ingestion  of  a 
large  amount  of  fluid;  or,  as  in  the  case  of  ether,  it  may  result 
from   a   secondary   dilatation   of   the   renal    arterioles.     Long- 


3  24 


PHARMACOLOGY   AND    THERAPEUTICS 


continued  alcohol  drinking  may  be  a  factor  in  the  production 
of  chronic  nephritis.  Warthin  says  he  has  never,  postmortem, 
seen  a  normal  kidney  in  an  alcoholic.  The  alcoholic  kidney  is  of 
the  sclerotic  type,  but  may  look  fairly  normal  to  the  naked  eye. 
It  is  often  not  evident  clinically. 

Bladder. — In  drunkenness  there  may  be  increased  secretion 
of  urine,  yet  at  the  same  time,  owing  to  depression  of  the  reflexes, 
there  may  be  inability  to  empty  the  bladder.  If  the  bladder 
becomes  greatly  distended,  the  urine  must  be  drawn  off  by 
catheter. 

The  Urine. — Reid  Hunt  has  shown  that  the  ethereal  sul- 
phates of  the  urine  are  trebled  in  amount  within  a  week  of  the 
commencement  of  regular  doses  of  alcohol,  and  that  the  neutral 
sulphur  is  decreased — "an  argument  that  alcohol  has  but  a 
limited  power  at  most  to  interfere  with  physiologic  oxidations." 

Excretion  of  Uric  Acid. — In  connection  with  the  effect  of 
alcohol  upon  physiologic  oxidations  by  the  liver,  and  because  of 
the  relation  of  alcoholic  drinks  to  gout,  the  uric-acid  factor  be- 
comes one  of  importance.  While  some  workers  (Norris  and 
Smith,  Beebe,  Rosenfeld)  have  found  after  alcohol  an  increase 
in  the  uric  acid  excreted  in  health,  others  (von  Noorden,  Leber, 
Rosemann,  Chittenden)  have  found  no  increase.  After  one  or 
two  bottles  of  wine  there  is  no  change  in  the  uric-acid  excretion 
(Rosemann),  but  after  beer,  a  purin-containing  liquid,  the  uric 
acid  rises.  (The  malt  liquors  contain  about  0.145  gm.  purins 
per  liter,  while  wines  are  free  from  purin  bases — Strauss.)  Man- 
del  found  that  while  refraining  from  food  a  young  man  excreted 
the  same  amount  of  uric  acid  when  he  took  900  c.c.  of  whisky 
as  when  he  took  nothing.  In  healthy  young  men  (students), 
unaccustomed  to  alcohol,  and  on  a  general  mixed  diet,  Beebe  got 
a  distinct  increase  in  the  uric  acid  after  alcohol,  but  no  increase 
when  the  men  were  placed  on  a  purin-free  diet.  These  experi- 
ments indicate  that  the  amount  of  exogenous  uric  acid,  that  derived 
from  purins  in  the  food,  may  or  may  not  be  increased  by  alcohol, 
but  thai  the  amount  of  endogenous  uric  acid,  that  derived  from  cell- 
metabolism,  is  uninfluenced.  Lusk  is  of  the  opinion  that  the 
increase  in  exogenous  uric  acid  may  be  due  to  an  interference  by 
alcohol  with  the  formation  of  the  normal  oxidizable  cleavage- 
products,  or,  in  other  words,  is  due  to  the  effect  of  alcohol  upon 
the  food,  rather  than  to  its  effect  upon  the  liver.  Beebe  thinks 
that  alcohol  interferes  with  the  uricolytic  power  of  the  liver. 

In  gout  the  results  of  experiments  have  not  been  uniform. 
Most  of  the  experiments  in  subjects  of  chronic  gout  have  been 
performed  during  the  quiescent  stage  of  the  gout,  and  show  a 
distinct  tendency  of  alcohol  to  lessen  the  excretion  of  uric  acid. 


ALCOHOL 


325 


But  whether  this  lessened  excretion  of  uric  acid  means  increased 
storage  in  the  system,  with  the  ultimate  production  of  a  new 
attack,  or  lessened  formation  of  uric  acid,  has  not  been  fully 
determined.  Yet  clinical  experience  favors  the  view  that  alcohol 
may  precipitate  an  attack  of  gout;  and  particularly  is  this  true 
of  the  malt  liquors  which  contain  0.145  gm-  °f  purin  bodies  per 
liter. 

Excretion  of  Sugar. — In  diabetes,  medicinal  or  dietetic  amounts 
of  alcohol  apparently  have  no  influence  upon  the  quantity  of 
sugar  excreted  or  upon  the  course  of  the  disease.  Hence  dis- 
tilled liquors,  and  sometimes  the  dry  wines,  are  allowed  in 
moderation  in  this  disease.  The  malt  liquors  and  sweet  wines 
are  forbidden  because  of  their  carbohydrate  ingredients  and 
acids,  and  not  because  of  their  alcohol.  In  severe  diabetes 
the  acids  of  wine,  and  probably  also  the  alcohol,  are  harmful. 
After  large  amounts  of  alcohol,  as  taken  in  a  debauch,  and  in 
chronic  alcoholism,  glycosuria  may  appear  even  in  a  non-diabetic; 
and  in  a  diabetic  there  may  be  not  only  increased  sugar  excre- 
tion, but  the  formation  of  acetone,  diacetic  acid,  and  betaoxy- 
butyric  acid,  with  the  development  of  pronounced  acidosis  and 
perhaps  fatal  diabetic  coma.  (The  writer  had  a  case  in  which 
fatal  diabetic  coma  followed  the  ingestion  of  a  quart  of  claret.) 
Toxicology. — In  susceptible  people  even  a  teaspoonful  of  a 
strongly  alcoholic  tincture  is  enough  to  flush  the  face  and  make 
the  head  feel  light.  In  unaccustomed  animals  Grahant  found 
that  6  parts  per  1000  in  the  blood  could  be  recovered  from. 

Acute  poisoning  is  drunkenness,  and  we  have  already  con- 
sidered its  cerebral  manifestations.  The  inattention  to  what 
is  going  on,  the  maudlin  intellect,  the  uncertain  speech,  the 
staggering  gait,  need  no  description.  Alcoholics  tend  to  be 
pugnacious,  lacrymose,  sleepy,  morose,  cheerful,  or  overpolite, 
according  to  their  temperaments,  or  owing  to  some  special 
action  of  the  liquor.  There  is  some  anesthesia,  so  that  the  pain 
of  an  injury  is  not  felt;  and  there  is  partial  muscular  relaxation, 
so  that  falls  are  less  likely  than  usual  to  result  in  broken  bones. 
This  stage  of  intoxication  persists  for  a  long  time,  but  eventually 
passes  into  that  of  stupor,  i.  e.,  deep  sleep  from  which  one  can  be 
awakened  with  difficulty.  When  aroused  from  this  alcoholic 
stupor,  the  patient  shows  stupidity  and  lack  of  intelligence, 
incoherent  speech,  relaxed  muscles,  and  incoordination,  so  that 
he  will  fall  limp,  or  at  least  have  difficulty  in  walking.  On 
being  left  alone  he  relapses  at  once  into  the  stuporous  sleep. 
This  state  distinguishes  alcoholism  from  morphine  poisoning,  in 
which  the  patient  on  being  aroused  shows  reasonable  intelligence, 


326  PHARMACOLOGY  AND   THERAPEUTICS 

can  speak  distinctly  and  answer  questions,  and  can  be  kept 
actively  walking. 

The  stupor  of  alcoholics  often  verges  closely  on  coma;  but 
even  at  this  stage  it  is  characteristic  of  alcohol  that  pressure  on 
the  supra-orbital  nerve  results  in  wincing  or  will  actually  arouse 
the  patient.  In  this  respect  alcoholic  stupor  or  coma  differs 
from  that  of  uremia,  diabetes,  opium-poisoning,  or  cerebral 
injury,  in  which  pressure  on  the  supra-orbital  nerve  meets  with 
no  response.  Following  the  onset  of  coma,  the  alcoholic  may 
readily  pass  into  collapse  and  die.  Death  is  not  infrequent  also 
from  a  fracture  of  the  skull  received  in  a  drunken  fall,  or  from 
pneumonia  brought  on  by  exposure.  Very  large  amounts  of 
strong  liquor  may  produce  death  from  reflex  shock.  Death  has 
frequently  occurred  from  drinking  large  quantities  quickly  as 
the  result  of  a  bet. 

Treatment. — It  is  the  usual  plan  to  give  plenty  of  fresh  air 
and  let  the  drunkard  sleep  it  off.  Occasionally,  especially  if  he 
has  smoked  freely,  the  patient  vomits  and  is  much  improved. 
In  some  cases  it  may  be  necessary  to  wash  out  the  stomach  or  to 
catheterize  the  bladder.  Caffeine  and  strychnine  are  anti- 
dotal. If  the  patient  goes  into  collapse,  the  regular  treatment 
for  collapse  is  indicated. 

After-effects. — The  systemic  after-effects  resemble  those  of 
ether  anesthesia;  viz.,  coated  tongue,  bad  taste  in  mouth,  loss 
of  appetite,  nausea,  retching,  vomiting,  constipation,  headache 
(bursting  head),  great  restlessness,  mental  depression  (remorse 
or  disgust  with  one's  self),  and  lack  of  energy.  There  are  regu- 
larly thirst  and  desire  for  more  liquor.  There  may  be  paralysis 
of  an  arm  (Sunday-morning  paralysis),  from  the  drunkard  hav- 
ing lain  upon  the  arm  in  such  a  way  as  to  cause  pressure  upon  the 
brachial  plexus. 

As  a  rule,  the  usual  morning  distress  may  be  treated  effec- 
tively with  aromatic  spirits  of  ammonia,  or  a  hot,  bitter,  and 
carminative  mixture.  This  is  known  as  a  "pick-me-up"  or 
"morning  tonic."  There  can  hardly  be  any  objection  to  giving 
teaspoonful  doses  of  an  alcoholic  tincture  even  though  one  is 
treating  alcoholism.     A  good  prescription  might  be : 

1$.    Tincl.  capsici 5j  (4  c.c.) 

Tinct.  lavandulae  comp oss  (15  c.c.) 

Spiritus  ammoniae  aromatici.  .  .  .q.  s.  ad  o'j  (60  c.c.) 

M.  et  Sig. — One  teaspoonful  in  water  every  one  or  two  hours. 

If  the  patient  is  very  restless,  bromides  may  be  given,  but  it 
must  be  remembered  that  it  is  irrational  to  give  strychnine  or 
nux  vomica  at  the  same  time.     A  dose  of  calomel  tends  to  lessen 


ALCOHOL 


327 


the  "bilious"  feeling;  and  lavage  or  a  hypodermatic  of  an  emetic 
dose  of  apomorphine,  repeated,  if  necessary,  will  clean  the 
stomach  when  there  is  distressing  retching  and  nausea. 

Chronic  Alcoholism. — Inebriates  may,  for  convenience,  be 
divided  into  three  classes,  viz.,  the  steady  drinkers,  the  periodic 
drinkers,  and  the  dipsomaniacs.  The  steady  drinkers  are 
always  under  the  influence  of  liquor,  though  not  of  necessity 
intoxicated.  The  periodic  drinkers  are  those  who  drink  to 
excess  at  intervals,  being  started  off  on  the  drinking  bout  by 
some  small  provocation.  They  have  little  will  power.  They 
soon  lose  their  sense  of  responsibility,  and  tend  to  drink  larger 
and  larger  quantities,  though  at  first  attending  to  business. 
Dipsomaniacs  are  the  victims  of  epileptic  insanity  (Diefendorf). 

In  dipsomania  the  impulse  to  drink  is  immediate  and  irresis- 
tible. It  comes  over  the  victim  like  a  paroxysm.  It  may  occur 
in  persons  who  hold  positions  of  responsibility;  and  these,  during 
the  attack,  may  perform  ruinous  acts  of  business,  commit  social 
offenses,  etc.  In  the  intervals  the  victims  may  drink  temper- 
ately or  not  at  all,  and  there  is  no  fear  that  the  sight  of  liquor 
will  bring  on  a  paroxysm.  In  the  attack  the  drinking  may  last 
only  a  day  or  two,  or  may  continue  in  gradually  increasing 
quantities,  or  with  partial  remissions,  for  weeks;  it  frequently 
terminates  in  prostration,  failure  of  the  patient's  stomach,  and 
nervous  breakdown.  The  patients  may  be  unable  to  remember 
where  they  have  been  or  what  they  have  done.  A  man  who 
had  not  drunk  for  some  time  was  left  a  fortune  on  condition 
that  he  refrained  from  drink  for  a  year.  This  acted  as  the 
exciting  cause  of  an  attack,  and  within  an  hour  of  the  reading  of 
the  will  he  was  intoxicated  (Crothers) . 

In  chronic  alcoholism  the  patient  is  bleary-eyed  and  nervous, 
has  a  tremor  of  the  hands,  lips,  and  tongue,  doesn't  care  to  go  to 
work,  smokes  to  excess,  and  has  a  great  thirst  for  liquors.  He 
may  have  various  gastro-intestinal  disturbances,  disgust  for 
food,  nausea,  retching,  vomiting,  constipation;  and  there  may  be 
an  alcoholic  gastritis,  with  irritability  of  the  stomach,  a  secretion 
of  large  quantities  of  thick  mucus,  and  a  gastric  juice  of  variable 
quality,  sometimes  highly  acid  and  sometimes  deficient  in  acid. 
There  may  be  a  swollen,  tender  liver.  The  nervous  system  is 
severely  upset,  and  there  may  be  mental  depression,  anxiety, 
lack  of  energy,  loss  of  will-power,  and  great  general  nervousness 
and  restlessness.  In  some  cases  there  is  a  peripheral  neuritis, 
usually  of  hands  or  feet,  but  sometimes  in  other  parts  of  the 
body,  with  tingling  and  numbness  or  acute  tenderness. 

The  patient  may  display  Korsakoff's  psychosis,  which  is  a 
condition  of  disorientation  with  the  memory  strikingly  at  fault. 


328  PHARMACOLOGY  AND   THERAPEUTICS 

The  patient  may  utterly  fail  to  remember  what  he  was  doing  an 
hour  or  a  few  minutes  before,  how  long  ago  he  came  to  the  hos- 
pital, what  is  his  business,  or  whether  he  is  married  or  not.  He 
thinks  the  physician  is  an  old  friend,  though  he  really  has  not 
seen  him  before;  and,  when  questioned,  will  answer  with  a  feeling 
of  absolute  certainty  what  is  obviously  untrue.  This  psychosis 
is  usually  accompanied  by  peripheral  neuritis. 

What  brings  the  patient  to  the  physician  is  mostly  either 
great  nervousness,  gastric  disturbance,  or  peripheral  neuritis. 
Some  men  seem  to  stand  a  daily  consumption  of  large  quantities 
of  liquor  for  a  very  long  time  without  having  occasion  to  visit  a 
physician;  others  succumb  readily  to  one  or  other  harmful  effect 
of  the  poison.  The  typical  chronic  alcoholic  gradually  loses  his 
mental  and  physical  vigor,  grows  careless  about  his  person  and 
his  habits,  and  becomes  a  relatively  useless  member  of  society. 
The  venules  of  nose  and  cheek  may  become  visible  from  'chronic 
dilatation,  the  eyes  are  watery,  injected,  and  with  a  far-away 
look,  the  sexual  powers  are  frequently  abolished  (azoospermia), 
and  the  organs  of  the  body  show  striking  pathologic  changes. 

Treatment  of  Chronic  Alcoholism. — According  to  the  circum- 
stances, the  indications  for  treatment  in  severe  outbreaks  are: 
(1)  To  check  the  craving  for  drink.  (2)  To  allay  nervousness 
and  overcome  insomnia.  (3)  To  supply  nourishment  and  get 
the  stomach  tolerant  to  food.     (4)  To  promote  elimination. 

1.  To  Check  the  Craving  for  Drink. — This  requires — (a) 
Gradual  withdrawal  of  the  alcoholic  drinks  and  (b)  their  replace- 
ment by  hot,  bitter  carminatives.  (See  Acute  Alcoholism.) 
Attempts  to  withdraw  the  liquor  suddenly  result  in  a  rebellious 
patient,  and  sometimes  in  serious  mental  and  nervous  mani- 
festations. For  the  gradual  withdrawal  of  liquor  there  are  two 
plans  in  common  use,  viz.: 

(a)  Allowing  one  ounce  of  whisky  for  each  dose,  the  interval 
between  the  doses  is  lengthened  each  time,  the  second  dose  being 
given  half  an  hour  after  the  first,  the  third  one  hour  later,  the 
fourth  two  hours  later,  etc. 

(b)  Using  a  bottleful  of  whisky,  a  drink  is  given  every  half- 
hour  or  hour,  but  after  each  dose  the  bottle  is  refilled  with  water, 
so  that  the  liquor  becomes  more  and  more  diluted.  After  a  time 
it  is  practically  all  water. 

2.  To  allay  nervousness  and  overcome  insomnia  the  favorite 
remedies  are  bromides  in  large  doses,  morphine  sulphate,  y^  grain 
(0.015  gm.)  by  hypodermatic,  hyoscine  bromide  or  atropine 
sulphate,  y^-g-  grain  (0.0006  gm.)  by  hypodermatic  or  mouth, 
paraldehyd,  2-4  drams  (8-15  c.c),  chloral  hydrate,  30  grains 
(2  gm.).     The  "narcotic"  method  of  keeping  the  patient  con- 


ALCOHOL  329 

stantly  asleep  for  from  twenty-four  to  thirty-six  hours  has  its 
strong  advocates,  and  even  the  rest  obtained  from  a  hypodermatic 
of  morphine  sulphate,  l/i  grain,  and  hyoscine  bromide,  y^-  grain, 
may  be  of  great  benefit. 

3.  To  supply  food,  small  quantities  of  hot  milk,  koumiss, 
oyster-stew,  junket,  calves'-foot  jelly,  etc.,  may  be  administered 
at  frequent  intervals.  As  soon  as  the  stomach  becomes  tolerant, 
milk- toast,  poached  egg  on  toast,  oysters,  etc.,  may  be  allowed. 

4.  To  promote  elimination,  valuable  measures  are  plenty  of 
fresh  air,  because  of  excretion  of  the  alcohol  by  the  lungs,  sweat- 
ing by  hot  baths,  or  a  Turkish  bath  if  patient  is  able  to  stand  it, 
and  vigorous  catharsis  with  compound  cathartic  pills,  or  calomel 
followed  by  citrate  of  magnesia. 

Delirium  tremens  ("the  horrors")  is  a  special  manifestation 
of  chronic  alcoholism.  It  rarely  occurs  except  after  continued 
heavy  drinking,  and  in  such  cases  may  be  brought  on  by  the 
sudden  withdrawal  of  the  alcohol  or  by  a  temporary  great  excess, 
or  by  pneumonia  or  by  traumatism,  e.  g.,  fracture  of  a  limb.  It 
is  characterized  by  horrible  hallucinations  of  sight  and  hearing. 
The  hallucinations  take  the  form  of  snakes,  rats,  things  crawling 
over  the  body,  or  people  with  harmful  intentions.  The  patient 
sees  them  coming  or  hears  voices.  He  shows  intense  activity, 
talking,  muttering,  crying  out,  attempting  to  get  out  of  bed,  or 
perhaps  to  escape  from  the  attendants.  Insomnia  is  almost 
complete,  and  there  may  be  a  temperature  of  1020  or  1030  F. 
Death  is  quite  a  frequent  outcome,  resulting  usually  either  from 
pneumonia,  from  traumatism,  or  from  collapse  brought  on  by 
the  alcoholic  depression  and  the  excessive  activity  or  struggling. 

The  treatment  is  that  for  chronic  alcoholism,  and  in  addition 
wise  restraint  and  close  watching  of  the  circulation  because  of 
the  tendency  to  collapse.  The  withdrawal  of  liquor  must  be 
managed  more  deliberately.  In  a  study  of  the  treatment  in 
500  cases  Ranson  (1909)  found  ergot  apparently  the  best  remedy. 
The  mortality  in  those  getting  ergot  was  21.6  per  cent,  below  the 
average. 

Late  in  the  course  of  lobar  pneumonia  in  persons  accustomed 
to  much  alcohol  there  is  sometimes  seen  a  peculiar  maniacal 
delirium  verging  on  delirium  tremens.  In  such  cases  the  delirium 
may  not  yield  until  good-sized  doses  of  whisky  or  brandy  are 
administered. 

The  cure  of  the  habit  depends  on  the  patient's  desire  for 
cure,  on  the  temperament  of  the  patient,  and  on  the  type  of  the 
drinker.  From  a  therapeutic  point  of  view  inebriates  may  be 
classed  as:  those  who  do  not  have  an  irresistible  craving  for 
alcohol,  and  those  who  do  have  the  craving  (Crothers).     The 


330  PHARMACOLOGY  AND  THERAPEUTICS 

former  drink  because  others  do,  or  from  bravado,  or  for  other 
reasons,  and  can  often  be  readily  induced  to  stop  drinking.  The 
latter  are  constant  drinkers,  periodic  excessive  drinkers,  or  dip- 
somaniacs. Their  treatment  is  the  same,  except  that  in  the  case 
of  the  dipsomaniac  restraint  is  a  requisite  at  the  time  of  the 
onset  of  the  attack.  Among  the  favorite  schemes  of  treatment 
are  hyoscine  bromide  or  hyoscyamine  or  atropine  sulphate,  twit 
grain  (0.0006  gm.)  thrice  daily,  which  causes  great  dryness  of 
the  throat  and  a  loss  of  taste  for  the  liquor;  strychnine  sul- 
phate, 3^  grain  three  times  a  day,  to  tone  up  the  system;  and 
hot  bitter  carminatives  to  supply  oral  and  gastric  stimulation. 
Doctoring  whisky  with  apomorphine  and  then  allowing  the 
patient  to  drink  whenever  he  wishes  is  another  method  in  vogue. 
The  nausea  and  vomiting  destroy  the  taste  for  liquor. 

Alexander  Lambert  administers  5  compound  cathartic  pills 
and  5  grains  of  blue  mass  every  twelve  hours  until  green 
stools  appear,  then  2  ounces  of  castor  oil.  During  the  process 
he  gives  to  nervous  or  elderly  persons  2  ounces  of  whisky  four  or 
five  times  in  the  first  twenty-four  hours,  then  only  strychnine  or 
digitalis,  and  a  sleep  mixture  of  chloral  hydrate,  morphine, 
tincture  of  hyoscyamus,  ginger,  and  capsicum.  If  the  patient 
has  an  intolerant  stomach,  he  gives  5  grains  of  sodium  bicar- 
bonate and  5  grains  of  compound  morphine  powder  every  two  or 
three  hours  for  two  or  three  doses.  During  the  whole  treatment 
he  gives  from  2  to  18  drops  every  hour  of  a  mixture  of  two  parts 
of  15  per  cent,  tincture  of  belladonna  and  one  part  each  of  the 
fluidextracts  of  hyoscyamus  and  xanthoxylum. 

The  Pathologic  Effects  on  Organs.— After  drinking  large 
quantities  has  been  the  habit  for  a  long  time,  certain  destructive 
changes  are  prone  to  appear  in  the  organs.  These  are  cirrhosis 
of  the  fiver  and  fatty  liver,  chronic  gastritis,  chronic  nephritis, 
myocarditis,  fatty  degeneration  of  the  heart,  arteriosclerosis, 
pulmonary  emphysema,  chronic  leptomeningitis,  peripheral 
neuritis,  various  spinal  and  cerebral  scleroses,  and  atrophy  of 
the  testicles.  In  the  brain-cells  the  chromatin  network  is 
replaced  by  fine  granules  or  lost  in  the  cytoplasm.  Though 
alcohol  is  undoubtedly  an  important  factor  in  the  production  of 
these  lesions,  it  is  believed  nowadays  that  the  influence  of  alcohol 
has  been  exaggerated,  and  that  there  are  other  important  causa- 
tive factors.  At  any  rate  such  lesions  are  not  infrequently  seen 
in  persons  who  have  not  been  alcoholic.  Simmonds,  of  Ham- 
burg, found  that  in  100  cases  of  cirrhosis  of  the  liver  14  were 
non-alcoholic.  In  309  autopsies  on  chronic  alcoholics  at  the 
Hafenkrankenhaus,  Fahr,  of  Hamburg,  found  striking  cirrhosis 
in  only  13  cases,  though  fatty  changes  were  usual.     In  30  per 


ALCOHOL 


331 


cent,  there  was  fatty  infiltration  of  the  heart,  in  20  per  cent, 
chronic  gastritis,  in  8  per  cent,  chronic  nephritis,  in  50  per  cent, 
chronic  leptomeningitis.  Arteriosclerosis  was  rather  less  com- 
mon than  among  other  cases  of  corresponding  age.  E.  B.  Phelps, 
speaking  from  an  insurance  point  of  view,  says  that  directly, 
indirectly,  or  even  remotely  alcohol  figures  in  only  5  or  6  per 
cent,  of  deaths. 

Richard  Cabot  has  looked  up  some  statistics  of  arteriosclerosis 
in  Boston.  Of  283  cases  of  chronic  excessive  alcoholism  under 
fifty  years  of  age,  only  6  per  cent,  showed  evidence  of  arterio- 
sclerosis. Of  45  cases  of  arteriosclerosis,  only  13  per  cent,  gave  a 
history  of  alcoholism.  Of  656  cases  of  arteriosclerosis  found 
postmortem,  only  95  (14.5  per  cent.)  were  under  fifty  years  of 
age,  and  of  this  95,  only  21  per  cent.,  appear  to  have  consumed 
alcohol  in  excess. 

In  regard  to  the  kidneys,  Hultgen  (1910)  reported  461  cases 
of  chronic  alcoholism  with  clinical  evidences  of  nephritis  in 
9.1  per  cent.,  and  albuminuria  in  5.2  per  cent.,  and  called  atten- 
tion to  the  report  of  Dickinson  in  Allbutt's  System  that  in  48 
autopsies  of  those  who  died  of  alcohol  there  was  no  greater 
proportion  of  contracted  kidneys  than  in  48  postmortems  of 
persons  of  the  same  age  who  were  not  alcoholics.  But  A.  S. 
Warthin  states  that  he  has  never  seen  a  normal  kidney,  post- 
mortem, from  an  alcoholic,  and  criticizes  Hultgen's  diagnosis  as 
clinical  and  not  histologic. 

Gideon  Wells  describes  the  alcoholic  kidney  as  of  the  "hog- 
back" type,  fat  and  rounded,  and  normal  looking,  but  really 
sclerotic  and  with  a  diminished  number  of  capable  glomeruli. 
In  the  author's  experience  it  may  fail  to  give  urinary  evidences 
unless  the  urine  is  examined  morning  and  evening  and  day  after 
day.  The  "wet  brain, "  or  edema  of  the  meninges,  is  common  in 
death  from  delirium  tremens. 

The  following  is  Welch's  summary  of  the  pathologic  changes 
in  the  rabbits  used  by  Friedenwald  (1905)  in  studying  experi- 
mental alcoholism.  The  daily  dose  was  5  to  8  c.c.  of  absolute 
alcohol  in  15  to  30  c.c.  of  water,  or  10  to  20  c.c.  of  whisky  diluted 
with  10  to  20  c.c.  of  water. 

1.  Animals   exhibit   marked   individual   differences   in    their 

susceptibility  to  the  injurious  effects  of  the  prolonged  ad- 
ministration of  intoxicating  doses  of  alcohol.  Some  rabbits 
given  intoxicating  doses  every  day  for  four  years  presented 
no  serious  anatomic  lesion  attributable  to  the  alcohol, 
while  to  similar  doses  others  succumbed  quickly. 

2.  The  most  common  pathologic  condition  is  a  fatty  metamor- 

phosis affecting  especially  the  cells  of  liver,  heart  muscle, 


332  PHARMACOLOGY    AND   THERAPEUTICS 

and  kidney,  the  lesion  speedily  disappearing  on  the  stop- 
page of  alcohol.     Necrosis  of  limited  groups  of  cells  in  liver 
and  kidneys  may  occur,  but  is  inconstant.     An  acute  or 
chronic  gastritis  may  appear,  but  is  often  absent.     Hyper- 
emia and  small  hemorrhages  may  occur,   especially  in 
stomach,  kidneys,  and  brain. 
3.  Alcoholic  intoxication  increases  the  susceptibility  of  ani- 
mals to  many  infections,  and  influences  unfavorably  the 
process  of  immunization.     Pregnant   rabbits   repeatedly 
intoxicated  are  prone  to  abort,  or  many  of  their  young 
die  in  a  few  days  after  birth. 
Reid  Hunt  (1907)  experimented  with  smaller  doses  through 
four  generations  of  guinea-pigs,  and  concluded  that  those  given 
a  few  cubic  centimeters  of  5  to  10  per  cent,  alcohol  with  their 
daily  food  grew  just  as  quickly,  reached  maturity  as  soon,  and 
were  just  as  fertile  as  those  with  no  alcohol.    They  showed  no 
symptoms,  no  loss  of  weight,  no  pathologic  changes.    Stockard, 
for  about  an  hour  each  day,  gave  alcohol  to  guinea-pigs  by  an 
inhalation  method,  up  to  the  stage  of  beginning  intoxication. 
Of  42  matings  of  such  alcoholic  guinea-pigs,  there  were  only  18 
young  born  alive,  and  of  these  only  7  survived  more  than  a  few 
weeks.     In  9  control  non-alcoholic  matings  there  were  9  living 
litters  of  17  individuals,  all  of  which  survived,  and  became  large, 
vigorous  animals. 

Tolerance. — That  tolerance  for  alcohol  is  readily  set  up  is 
every-day  experience,  and  this  seems  to  be  due  partly  to  an  in- 
creased power  to  oxidize  the  drug,  and  partly  to  an  increased 
resistance  of  the  cells  to  the  harmful  effects  of  the  alcohol.  As 
in  such  cases  oxidation  begins  promptly,  a  great  deal  of  alcohol 
may  be  consumed  without  signs  of  intoxication.  In  dog  experi- 
ments a  much  larger  percentage  of  alcohol  in  the  blood  can  be 
borne  by  those  in  which  tolerance  has  been  established. 

Resistance  to  Disease. — There  is  evidence — (1)  That  medicinal 
quantities  of  alcohol  increase  the  susceptibility  to  bacterial  in- 
vasion or  increase  the  danger  of  toxemias  in  acute  illness;  and 
there  is  no  doubt  that  the  taking  of  alcohol  in  large  quantities 
day  after  day  for  many  years  results  in  impairment  of  the  body 
structures,  lessens  resistance  to  many  infections,  influences  un- 
favorably the  processes  of  immunization,  and  diminishes  the  heal- 
ing power  of  injured  tissues.  There  is  a  well-recognized  high 
mortality  among  alcoholics  in  pneumonia  and  tuberculosis. 
Laitinen  reports  a  greater  susceptibility  to  infection  and  greater 
mortality  if  much  alcohol  is  used,  but  not  much  from  the  pro- 
longed use  of  small  quantities  (0.1  c.c.  per  kilo,  i.e.,  15  c.c.  whisky 
for  a  man). 


ALCOHOL  333 

Rubin  found  that  a  hypodermatic  of  alcohol,  ether,  or  chlor- 
oform would  render  rabbits  more  susceptible  to  streptococcus 
and  pneumococcus  infections;  Stewart,  that  a  small  amount  of 
alcohol  lowers  the  opsonic  index  to  the  bacillus  tuberculosis  and 
streptococcus,  and  Graham  that  animals  given  alcohol  or  ether 
succumb  more  readily  to  experimental  infection  than  controls, 
especially  in  those  diseases  of  which  the  immunity  is  chiefly 
phagocytic. 

Alcohol  in  mildly  intoxicating  quantities  for  several  days 
after  the  injection  of  the  antigen  retards  the  formation  of  the 
antibodies  (Miiller,  1904;  Wirgin,  1905);  but  the  results  of 
others'  experiments  seem  to  indicate  a  favorable  action  in  the 
formation  of  antibodies  from  a  single  mildly  toxic  dose  of  alco- 
hol at  or  near  the  time  the  antigen  is  introduced.  Laitinen  found 
it  difficult  to  immunize  alcoholized  animals  to  diphtheria  toxin. 
Parkinson  found  that  a  small  dose  in  rabbits  might  stimulate 
the  production  of  antibodies  temporarily  and  that  it  lessened 
the  reacting  mechanism  to  vaccines ;  that  a  large  dose  will  lower 
the  opsonic  index  for  twenty-four  hours,  and  that  continued 
moderate  doses  cause  a  permanent  lowering  of  the  opsonic  index. 
It  has  no  action  on  phagocytic  activity  if  present  in  a  strength 
below  12.5  per  cent. 

Preventives. — Leonard  Hill  reports  that  in  alcohol  poisoning 
fatty  infiltration  of  the  liver  is  prevented  by  feeding  glycogen- 
builders,  i.  e.,  carbohydrates.  Dogs  which  on  pure  fat  diet  put 
on  25  per  cent,  of  dry  liver  substance  as  fat,  have  this  per  cent, 
lowered  to  one-half  or  less  by  the  feeding  of  glycogen-builders 
at  the  same  time.  Von  Noorden  noted  that  the  percentage  of 
fat  in  both  heart  and  liver  of  starved  dogs  increases  in  a  few  days 
from  alcohol,  but  that  this  effect  is  prevented  by  sugar.  Similar 
though  less  marked  protection  of  the  liver  has  been  reported  from 
sodium  bicarbonate. 

Therapeutics. — External. — As  antiseptic,  as  in  cleansing  sur- 
geon's hands  or  skin  of  patient.  As  cooling  lotion  in  headache 
or  in  itching  or  for  bruises  (eau  de  cologne,  spirit  of  camphor, 
witch-hazel,  or  tincture  of  arnica).  For  rubbing  the  body  of  an 
invalid,  50  to  95  per  cent,  alcohol  is  very  refreshing,  and  in  fever 
is  cooling.  As  anidrotic  in  sweating  of  the  hands  and  feet  and 
in  the  night-sweats  of  tuberculosis.  To  harden  the  skin,  as  when 
bed-sores  are  threatened.  In  refractory  trigeminal  neuralgia,  15 
minims  (1  c.c.)  may  be  injected  into  the  nerve. 

As  a  preventive  of  carbolic-acid  burns,  alcohol  is  the  best  remedy. 
Its  affinity  for  the  phenol  being  greater  than  that  of  the  tissues, 
it  prevents  penetration  of  the  carbolic.  When  the  carbolic  is 
swallowed,  alcohol  is  best  given  in  the  form  of  whisky,  but  it 


334  PHARMACOLOGY    AND    THERAPEUTICS 

should  be  at  once  washed  out;  for  though  it  lessens  the  local 
effect,  it  may  increase  the  absorption  of  the  carbolic  and  hence 
the  systemic  poisoning. 

Alimentary  Tract. — For  their  effect  on  appetite  and  digestion 
alcoholic  drinks  may  be  employed  in  convalescence  and  debility, 
and  in  conditions  of  diminished  gastric  secretion;  for  their  car- 
minative action  in  flatulence  and  colic;  for  their  reflex  stimulat- 
ing effect  in  faintness  and  fainting.  For  the  carminative  and 
reflex  stimulating  effect  only  the  fortified  wines  and  distilled 
liquors  are  of  avail.  Ice-cold  brandy  and  champagne,  especially 
the  latter,  because  of  the  CO2  it  contains,  are  employed  in  sea- 
sickness and  other  forms  of  intractable  nausea  and  vomiting. 
Brandy  is  a  favorite  remedy  in  summer  diarrhea. 

For  Systemic  Effect. — Alcohol  is  used : 

1.  To  prevent  or  check  a  cold  after  exposure. 

2.  To  furnish  food  and  stimulation  in  depressed  conditions, 
and  in  convalescence  from  acute  illness  (milk-punch). 

3.  As  a  narcotic  or  sedative  in  states  of  nervousness,  restless- 
ness, or  delirum;  in  the  delirum  of  alcoholics  it  may  be  especially 
necessary. 

4.  As  hypnotic  in  mild  chronic  forms  of  insomnia,  as  from 
mental  work  late  at  night  or  continued  nervous  strain  (beer,  ale, 
or  whisky  taken  at  bed-time). 

5.  In  fever,  as  antipyretic,  as  food,  and  as  narcotic  to  allay 
nervousness  and  restlessness  and  promote  quiet  and  sleep,  but 
it  lowers  resistance. 

For  energetic  action  whisky  and  brandy  are  mostly  employed. 
In  surgical  shock  it  tends  to  decrease  the  already  lowered  blood- 
pressure  (Crile) ;  but  in  mild  degrees  of  shock,  where  conscious- 
ness is  not  abolished,  as  in  emotional  shock  or  mild  trauma,  the 
condition  may  be  improved  both  by  the  reflex  stimulation  of 
the  surface  irritant  action  and  by  the  narcotic  effect  upon  the 
excited  mind. 

The  use  of  alcohol  in  medicine  has  become  very  much  limited 
in  recent  years,  and  we  no  longer  see  a  pneumonia  patient  del- 
uged with  one  or  two  pints  of  whisky  a  day,  or  one  with  tuber- 
culosis feeding  on  innumerable  milk-punches.  That  its  real  value 
in  many  cases  is  due  to  its  narcotic  or  sedative  effect  has  not  been 
fully  appreciated. 

Contraindications. — Gastric  ulcer,  gastric  hypersecretion,  hy- 
perchlorhydria,  intestinal  autointoxication,  cirrhosis  of  the  liver, 
nephritis,  cystitis,  urethritis,  chronic  eczema,  and  gout.  In  dia- 
betes the  sweet  wines  and  malt  liquors  are  distinctly  contraindi- 
cated,  and  it  is  open  to  question  if  even  a  dry  wine  should  be 
allowed,  because  of  its  acids. 


HYPNOTICS  335 

Where  it  is  known  that  the  patient  has  been  an  alcohol 
habitue,  it  is  criminal  to  prescribe  an  alcoholic  drink,  and  it  is 
the  duty  of  the  physician  to  consider  well  before  prescribing  any 
medicine  with  a  distinctly  alcoholic  or  vinous  flavor.  In  sickness 
it  is  equally  imperative  to  use  judgment  before  cutting  off  the 
alcohol  from  a  drinker;  for  it  will  not  do,  for  example,  to  stop 
the  whisky  of  a  chronic  drinker  during  an  attack  of  pneumonia. 

METHYL  ALCOHOL 

Methyl  alcohol,  or  wood  alcohol,  CH3OH,  is  not  employed 
as  a  remedy,  but  is  of  interest  because  of  the  number  of  cases  of 
serious  poisoning  following  its  use.  Its  local  and  central  actions 
are  similar  to  those  of  ethyl  alcohol,  and  it  can  produce  a  somewhat 
similar  intoxication,  though  the  onset  is  slower  and  the  depression 
or  narcotic  condition  more  prolonged.  But  two  striking  differ- 
ences are  that  it  is  not  readily  excreted  and  is  not  fully  oxidized. 
Indeed,  its  products  in  the  body  are  formic  acid  and  formaldehyd, 
and  it  is  thought  that  these  substances,  or  perhaps  acetone,  and 
other  bodies  always  present  in  the  commercial  article,  may  ac- 
count for  its  especially  deleterious  effects.  These  effects  are  of 
two  kinds,  viz.,  atrophy  of  the  optic  nerve,  with  permanent 
blindness,  and  depression  of  cardiac  and  voluntary  muscle,  re- 
sulting in  death. 

Buller  and  Wood  collected  54  cases  of  blindness  in  the  United 
States  and  Canada,  some  of  which  died.  A  great  many  cases  of 
either  blindness  or  death  have  since  been  reported.  After  one 
celebration  on  doctored  whisky  at  Dorpat,  Russia,  16  men  and 
1  woman  died,  and  3  men  became  blind.  At  Stryker's  Farms, 
near  New  York,  25  died  from  drinking  a  cheap  whisky  made  of 
methyl  alcohol.  In  the  Berlin  municipal  lodging-house,  in  the 
month  of  December,  1.91 1,  there  were  70  sudden  deaths  due  to 
wood  alcohol  in  cheap  spirits.  There  are  many  other  instances  of 
recent  date. 

These  deaths  have  usually  followed  debauches  with  adulter- 
ated whisky.  But  many  instances  of  blindness  have  come  from 
hair-tonics,  bay-rum,  cologne- water,  essence  of  ginger,  and  other 
pharmaceuticals  in  which  wood  alcohol  has  been  substituted  for 
grain  alcohol.  Because  of  many  cases  in  New  York  city,  the 
Health  Department  has  an  ordinance  forbidding  the  use  of  methyl 
alcohol  in  any  preparation  for  human  use,  either  externally  or 
internally. 

Hypnotics 
A  hypnotic  is  a  remedy  employed  to  induce  or  to  maintain 
sleep.    Leonard  Hill  summarizes  as  follows  the  facts  which  are 
known  concerning  sleep: 


336  PHARMACOLOGY  AND  THERAPEUTICS 

i.  Respiration. — (a)  The  number  per  minute  remains  unal- 
tered; the  movement  becomes  shallow  and  thoracic  in  type; 
(b)  the  amount  of  inspired  air  per  minute  is  lessened  by  from 
one-half  to  two-thirds;  (c)  the  output  of  C02  is  diminished  by 
one-half  to  two-thirds. 

2.  Circulation. — (a)  The  blood  congests  in  the  limbs;  (b)  the 
venous  system  is  engorged;  (c)  the  arterial  pressure  falls;  (d)  the 
pulse-rate  diminishes;  and  (e)  the  velocity  of  blood-flow  decreases. 

3.  Temperature. — The  temperature  falls  during  the  night. 
The  production  of  heat  is  estimated  to  diminish  by  from  one- 
half  to  two-thirds. 

4.  Nervous  System. — (a)  The  blood-flow  through  the  brain  is 
diminished;  (b)  the  acidity  of  the  cortex  decreases;  (c)  the  ex- 
citability of  consciousness  to  external  stimuli  steadily  decreases 
during  the  first  one  to  two  hours  of  sound  sleep.  After  that 
period  the  excitability  rapidly  becomes  almost  as  great  as  it  is 
toward  the  end  of  sleep;  and  (d)  consciousness  alone  seems  to  be 
abrogated  during  sleep.  The  nerves  and  the  special  senses  con- 
tinue to  transmit  impulses  and  produce  reflex  movements. 

Verwom's  Theory. — Sleep,  as  pointed  out  by  Verworn,  is 
entirely  different  from  narcosis.  Sleep  comes  because  of — (1) 
The  lessened  irritability,  i.  e.,  fatigue,  of  the  cells  of  the  cerebral 
cortex  which  results  from  work;  and  (2)  the  removal  of  external 
stimuli,  as  noise,  lights,  etc.  Narcosis  comes  from  direct  and 
deliberate  depression  of  the  cells  of  the  cerebral  cortex.  In  sleep 
the  cells  recover  from  fatigue,  regain  their  lost  irritability,  and 
are  restored  to  their  full  capacity  for  work;  in  other  words,  sleep 
implies  restitution.  In  narcosis,  on  the  other  hand,  there  is  no 
restitution,  and  the  cells  lose  their  irritability  and  go  through 
the  stages  of  fatigue  production.  A  narcotic  is  prone  to  be  fol- 
lowed by  sleep  because  it  produces  fatigue  of  the  cells,  and  when 
a  narcotic  substance  is  given  to  produce  sleep  (i.e.,  a  hypnotic), 
it  does  so  by  depressing  the  cells  and  thus  reducing  the  excita- 
bility of  the  cerebral  cortex  which  is  preventing  sleep.  The 
depression  of  the  cells  thus  produced  may  then  be  followed  by 
restorative  sleep,  but  the  hypnotic  does  not  directly  or  primarily 
induce  natural  sleep. 

If  too  much  of  the  hypnotic  is  given,  the  primary  narcosis  is 
not  followed  by  restorative  sleep,  but  continues  for  a  long  time, 
and  results  in  fatigue  of  the  cerebral  cells  instead  of  restoration. 
This  effect  is  sometimes  seen  during  the  following  day,  especially 
in  old  people,  and  it  shows  in  mental  and  physical  depression  and 
tiredness. 

Hypnotic  measures  include  drugs,  hot  baths,  the  establishment 
of  proper  conditions  for  sleeping,  etc.    They  promote  sleep,  either 


HYPNOTICS  337 

by  lessening  cerebral  congestion,  by  producing  cerebral  anemia, 
or  by  directly  depressing  the  cerebral  cells.  The  hypnotic  drugs 
act  essentially  in  the  last  way,  the  sleep  being  the  result  of  di- 
minished mental  activity  and  restlessness,  and  dulling  of  the  per- 
ceptions. In  other  words,  hypnotic  drugs  are  narcotic.  Their 
action  resembles  somewhat  that  of  the  general  anesthestics,  but 
is  slower  in  its  onset,  less  powerful,  and  more  lasting,  and  is  not 
intended  to  produce  a  deep  stage  of  narcosis.  It  goes  without 
saying  that  the  drugs  suitable  for  use  as  hypnotics  must  be  capa- 
ble of  depressing  the  cerebrum  to  the  sleep  stage  without  any 
essential  depression  of  the  vital  medullary  centers.  All  hypnotics 
act  with  more  power  at  the  usual  sleep  time,  and  if  a  patient  is 
in  bed  in  a  quiet,  darkened  room.  In  fact,  if  the  patient  is  about 
and  active,  the  ordinary  dose  of  a  hypnotic  may  scarcely  produce 
even  drowsiness. 

Because  of  the  peculiar  nature  of  insomnia,  the  taking  of 
hypnotic  drugs  may  in  many  cases  lead  to  a  drug  habit.  On  this 
account  a  physician  should  avoid,  if  possible,  the  repeated  ad- 
ministration of  hypnotics  for  long  periods,  especially  with  neu- 
rotic patients,  and  should  endeavor  to  keep  the  drug-taking  under 
his  own  control.  If  a  hypnotic  drug  seems  imperative,  the  pre- 
scription should  be  changed  from  time  to  time;  but  it  is  often 
possible,  by  very  simple  measures,  to  improve  the  patient's  sleep- 
ing tendencies,  and  so  escape  the  necessity  for  the  use  of  drugs. 

Some  simple  hypnotic  measures  are: 

i.  Avoidance  of  conditions  that  promote  wakefulness,  such 
as  noisy  or  disturbing  surroundings,  active  mental  work 
just  before  going  to  bed,  exciting  plays,  emotional  music, 
or  caffeine  drinks  in  the  evening. 

2.  Establishment  of  conditions  that  favor  mental  relaxation 
and  sleepiness,  such  as  a  walk  in  the  open  air  in  the  evening 
or  a  hot  bath.  If  there  seems  to  be  a  psychic  demand  for 
some  drug,  but  no  physical  demand,  a  harmless  remedy, 
such  as  sugar  of  milk  in  capsules,  or  tablet  triturates  or 
pills  (prescribed  as  "Pil.  Blank"),  or  a  bitterish  dose  by 
mouth,  or  a  hypodermic  of  plain  water  (thought  by  the 
patient  to  be  morphine) ,  may  be  effective. 

There  are  three  types  of  cerebral  depression  which  may  be 
desired  from  hypnotic  drugs. 

i.  Brief,  mild  depression — to  induce  the  onset  of  sleep  only, 
the  sleep  then  tending  normally  to  continue  for  the  usual 
length  of  time;  a  glass  of  ale,  for  example,  when  a  person 
is  fatigued  but  cannot  get  to  sleep  because  of  excitement, 
mental  activity,  or  restlessness. 


338  PHARMACOLOGY  AND   THERAPEUTICS 

2.  Prolonged  mild  depression — both  to  induce  sleep  and  to 

maintain  it  for  a  length  of  time,  when  the  normal  tendency 
to  sleep  seems  to  be  absent,  or  when  the  perceptive  faculties 
are  overkeen,  so  that  waking  is  easy,  as  in  fevers,  neuras- 
thenia, various  neuroses,  some  forms  of  habitual  insomnia, 
etc.  An  occasional  drug  for  this  purpose  might  be  chloral 
hydrate  or  veronal. 

3.  Prolonged  depression  with  analgesia— -to  produce  and  main- 

tain quiet  and  sleep,  in  spite  of  pain  or  other  powerful 
factors  which  tend  to  keep  the  patient  awake,  e.  g., 
morphine.    Drugs  which  abolish  pain  are  "  analgesic." 

A  hypnotic  must  be  considered  as  to  its  effectiveness,  its 
rapidity  of  action,  its  length  of  action,  its  power  to  overcome 
pain,  and  its  safety.  We  might,  for  practical  purposes,  divide 
the  hypnotics  in  common  use  into — (a)  Those  which  do  not  abol- 
ish pain,  as  chloral  hydrate,  (b)  Those  which  do  abolish  pain, 
as  morphine. 

A.  Hypnotics  Which  Do  Not  Abolish  Pain 
CHLORAL  HYDRATE 

Chloralum  hydratum,  or  hydrated  chloral,  CCI3COH+H2O,  is 
prepared  by  passing  chlorine  gas  through  absolute  alcohol  and 
precipitating  by  water.  It  occurs  in  the  form  of  hygroscopic 
crystals  with  bitter,  caustic  taste  and  penetrating  odor.  It  is 
freely  soluble  in  water,  alcohol,  ether,  chloroform,  and  the  fixed 
and  volatile  oils,  and  liquefies  when  mixed  with  camphor,  men- 
thol, or  thymol.  In  strongly  alkaline  liquids  it  is  decomposed, 
chloroform  being  set  free.  In  a  strength  of  carbonated  alkali  the 
same  as  that  of  the  blood  it  remains  unchanged.  The  dose  is  15 
grains  (1  gm.).  There  are  no  preparations  except  the  National 
Formulary  liquid,  chloral-camphor,  made  by  mixing  equal  parts 
of  chloral  and  camphor,  and  used  externally  as  a  counterirritant. 

Pharmacologic  Action. — Microorganisms. — Having  some  an- 
tiseptic power,  it  is  sometimes  added  to  urine  as  a  preservative. 

External. — Applied  to  the  skin  it  is  counterirritant,  producing 
reddening  and  warmth;  there  is  slight  local  anesthesia  from  depres- 
sion of  the  ends  of  the  sensory  nerves.  If  applied  continuously  in 
concentrated  form,  it  will  produce  death  of  tissue,  with  sloughing 
and  the  formation  of  an  ulcer.  This  is  because  of  its  contained 
chlorine,  which  gives  it  an  especially  destructive  action  upon 
protoplasm. 

Alimentary  Tract. — The  taste  is  characteristic  and  unpleasant. 
Small  doses  are  carminative,  but  doses  large  enough  for  hypnotic 


CHLORAL  HYDRATE  339 

effect  are  irritant,  and  unless  well  diluted  may  induce  nausea  and 
even  vomiting. 

Absorption  is  fairly  rapid  from  the  stomach  and  intestines. 

Nervous  System. — In  hypnotic  doses  chloral  hydrate  fairly  rap- 
idly induces  a  mild  but  prolonged  cerebral  depression,  accom- 
panied by  the  phenomena  of  natural  sleep,  and  it  is  a  very  reliable 
hypnotic.  The  pulse  and  respiration  are  somewhat  slowed,  the 
pupil  is  in  midcontraction,  the  C02  of  the  blood  is  reduced,  as  in 
sleep,  and  the  patient  may  be  fairly  easily  aroused  by  noises  or 
pain  or  other  sleep  antagonists. 

From  therapeutic  amounts  there  is  no  essential  analgesia,  so 
.that  pain  is  not  abolished,  and  in  animal  experiments  it  is  found 
that  there  must  be  profound  narcosis  before  there  is  any  per- 
ceptible diminution  in  the  response  to  painful  stimuli.  The  re- 
flexes are  somewhat  depressed,  but  not  enough  by  safe  amounts 
to  make  the  drug  more  than  weakly  antidotal  to  the  convulsions 
of  eclampsia,  tetanus,  and  strychnine  poisoning.  In  dogs  chloral 
is  antidotal  to  strychnine,  for  dogs  can  take  a  much  larger  dose 
of  chloral  without  dangerous  depression.  Pringard  gave  0.25 
gm.,  and  Hopkins  1.5  gm.,  per  kilo  without  death. 

From  poisonous  doses  there  is  profound  stupor,  diminished 
excitability  of  the  motor  areas  of  the  brain,  as  shown  in  experi- 
ments with  dogs,  depressed  pain  sense,  and  diminished  reflexes, 
so  that  there  is  more  or  less  muscular  relaxation.  The  patient 
passes  through  stages  similar  to  those  from  chloroform,  and 
may  pass  to  a  state  of  surgical  anesthesia  (coma) ,  with  abolition 
of  consciousness  and  of  the  reflexes,  but  in  imminent  danger  of 
collapse. 

The  peripheral  nerves  are  not  affected  by  systemic  administra- 
tion. From  local  application  there  is  slight  depression  of  the 
sensory  nerve-endings.    (See  Local  Action.) 

Respiration. — In  the  sleep  produced  by  therapeutic  doses  the 
breathing  is  slowed  as  in  ordinary  sleep;  while  from  poisonous 
doses,  through  depression  of  the  respiratory  center  and  the  failure 
of  the  circulation,  the  breathing  becomes  slow  and  shallow. 
Death  takes  place  usually  from  failure  of  the  respiration,  but 
restoration  by  artificial  respiration  is  impossible  because  of  the 
feeble  circulation. 

Circulation. — The  addition  of  chloral  hydrate  to  the  fluid 
used  in  perfusing  an  isolated  heart  induces  a  few  strengthened 
beats,  presumably  from  protoplasmic  irritation,  and  then  a  slow- 
ing of  the  heart,  with  gradually  weakening  contraction  in  systole 
and  increasing  relaxation  in  diastole.  The  heart  loses  its  tone 
and  its  contractility,  and  soon  stops  with  the  ventricles  widely 


340  PHARMACOLOGY   AND    THERAPEUTICS 

dilated  in  diastole.    These  effects  are  due  to  direct  depression  of 

the  muscle. 

On  measuring  the  outflow  of  a  perfused  viscus  or  severed  limb, 
the  addition  of  a  solution  of  chloral  hydrate  causes  a  momentary 
diminution  of  outflow,  showing  contraction  of  the  arteries,  but 
this  is  followed  quickly  and  persistently  by  an  increased  outflow, 
so  that  the  essential  peripheral  action  is  dilatation  of  the  arteries. 
This  is  brought,  about  by  a  direct  depression  of  the  arterial  mus- 
cles. In  the  intact  animal  a  large  dose  also  depresses  the  vaso- 
constrictor center. 

Chloral  hydrate,  therefore,  in  good-sized  dose,  is  a  circulatory 
depressant,  acting  most  strikingly  to  depress  the  heart  muscle, 
but  also  to  depress  the  vasoconstri<  tor  center  and  the  muscles  of 
the  arteries.  The  vagus  center  is  also  depressed,  but  in  spite  of 
this  the  heart  is  slowed  from  muscular  weakening. 

In  the  sleep  from  a  single  safe  hynotic  dose  it  is  observed  that 
the  slowing  of  the  heart  and  the  lowering  of  blood-pressure  are 
not  any  greater  than  those  in  ordinary  sleep,  i.  c.  the  circulatory 
depression  is  not  manifest;  while  with  only  slightly  larger  than 
ordinary  therapeutic  doses  the  circulatory  depression  may  super- 
vene, so  that  the  drug  becomes  distinctly  dangerous.  Archan- 
gelsky  found  that  the  blood  of  a  dog  in  deep  chloral  sleep  contained 
0.03-0.05  per  cent,  of  chloral  hydrate,  that  at  0.056  per  cent,  the 
arterial  pressure  had  fallen  to  one-half,  and  at  0.07  per  cent,  the 
breathing  -topped.  There  are  reports  of  death  from  only  double 
the  dose  to  which  the  patient  or  habitue  had  been  accustomed. 
Hence  the  margin  of  safety  with  chloral  is  a  narrow  one. 

When  taken  at  regular  intervals  for  a  long  period  chloral 
tends  to  lessen  the  viscosity  of  the  blood,  to  destroy  the  red  and 
white  blood-corpuscles,  and  to  cause  fatty  degeneration  in  heart 
and  arteries.  Even  small  doses  cause  dilatation  of  the  cutaneous 
arterioles,  with  flushing  of  the  skin. 

Temperature. — On  account  of  diminished  activity  there  is 
lessened  production  of  heat,  and  on  account  of  the  dilatation  of  the 
cutaneous  vessels  there  is  increased  dissipation  of  heat,  so  chloral 
tends  to  lower  temperature.  It  is  not,  however,  employed  as  an 
antipyretic.     A  subnormal  temperature  is  seen  in  poisoning. 

Elimination. — When  warmed  with  strong  alkalies  in  a  test 
tube,  chloral  readily  liberates  chloroform,  yet  in  a  solution  of 
sodium  carbonate  of  the  strength  in  the  blood  it  does  not  de- 
(  ompose  at  the  temperature  of  the  body;  and  it  does  not  liberate 
chloroform  in  the  blood,  for  none  has  been  found  either  in  the 
blood  or  in  the  breath  (Hammarsten,  etc.).  Instead  of  this  the 
chloral,  which  is  trichloraldehvd.  becomes  trichlorethyl-alcohol, 
and  combines  with  glycuronic  acid  to  form  the  non-toxic  uro- 


CHLORAL   HYDRATE  341 

chloralic  acid  ( trichlorethyl-glycuronic  acid).  This  is  excreted 
slightly  by  the  stomach,  but  mostly  by  the  kidneys.  A  small 
amount  of  chloral  may  be  excreted  unchanged.  In  the  urine, 
urochloralic  acid  is  said  to  give  a  reaction  with  Fehling*s  solution 
similar  to  that  of  glucose,  but  in  a  large  number  of  tests  of  the  urine 
from  patients  taking  from  10  to  120  grains  of  chloral  hydrate  a 
day  the  writer  was  unable  to  get  a  single  reduction  of  the  Fehling's, 
except  after  boiling  for  a  minute  or  two.  The  reducing  substance 
is  readily  distinguished  from  dextrose,  as  it  turns  the  plane  of 
polarized  light  to  the  left  and  does  not  ferment  with  yeast. 

Metabolism. — Chloral  hydrate,  chloroform,  and  other  chlorine- 
containing  bodies  of  the  methane  group  are  marked  protoplasm 
poisons;  and  after  chloral  there  is  evidence  of  increased  protein 
destruction,  with  the  appearance  in  the  urine  of  increased  ni- 
trogen, phosphorus,  and  sulphur,  the  destructive  products  being 
less  completely  oxidized  than  normally.  The  effects  are  much  less 
pronounced  than  from  chloroform.  There  is  a  slight  tendency 
to  fatty  degeneration  in  the  liver,  heart,  and  arteries,  especially 
in  chronic  chloral  takers. 

In  a  study  of  the  effects  on  metabolism  J.  G.  Hopkins  (191 1) 
gave  dogs  as  much  as  1.5  gm.  per  kilo  as  the  daily  dose,  enough 
to  produce  profound  narcosis  and  anesthesia.  He  found  no  areas 
of  necrosis  and  only  occasional  very  slight  fatty  changes  in  the 
liver,  of  the  type  produced  by  chloroform,  and  no  changes  at  all 
in  the  kidneys. 

Uterus. — Chloral  is  said  to  promote  relaxation  of  the  cervix 
in  the  first  stage  of  labor,  without  very  greatly  lessening  the 
normal  uterine  contractions. 

Untoward  Effects. — Occasionally,  owing  to  idiosyncrasy,  a 
hypnotic  dose  results  in  excitement  and  headache  instead  of 
sleep;  or  in  a  skin  rash  of  the  types  of  erythema,  urticaria,  pur- 
pura, and  bullae;  or  in  temporary  gastro-intestinal  disturbances. 

Toxicology. — Acute  Poisoning. — The  condition  is  one  of  pro- 
found narcosis,  with  diminution  or  abolition  of  the  reflexes, 
muscular  relaxation,  and  early  and  marked  respirator}*  and  cir- 
culatory depression.  It  may  be  distinguished  from  morphine 
poisoning  by  the  absence  of  very  slow  respiration  and  by  the 
circulatory  depression,  the  muscular  relaxation,  the  marked 
diminution  or  abolition  of  the  reflexes,  and  the  pupil  in  midcon- 
traction.  The  many  cases  reported  of  collapse  from  very  little 
above  the  hypnotic  dose  show  that  the  drug  is  a  dangerous  one. 
Death  has  resulted  from  1  dram  (4  gm. )  given  at  one  dose,  though 
2  or  3  drams  (8-12  gm. )  have  been  taken  in  twenty- four  hours 
without  apparent  toxic  effects.  Amounts  of  720  grains  (45  gm.) 
in  forty-two  hours  (Geis),  and  640  grains  (41  gm.)  in  three  days 


342  PHARMACOLOGY  AND   THERAPEUTICS 

(Rogers),  have  been  recovered  from.  The  treatment  is  that  for 
collapse,  the  preferred  drugs  being  caffeine,  atropine,  strychnine, 
and  camphor.  Artificial  respiration,  oxygen,  and  other  measures 
may  be  employed.  The  greatest  care  is  necessary  to  avoid  exer- 
tion on  the  part  of  the  patient,  as  this  tends  to  precipitate  heart 
failure. 

Chronic  Poisoning  or  Chloral  ism. — The  chloral  habit  is  not 
uncommon,  especially  among  neurotic  persons  and  brain-workers. 
The  pronounced  habitue  becomes  thin  and  anemic,  has  gastric 
disturbances,  loss  of  appetite,  constipation,  mental  depression, 
lack  of  energy,  weakened  will  power,  and  various  nervous  symp- 
toms. Skin  eruptions  may  appear,  and  there  is  a  possibility  of 
fatty  degeneration  of  heart,  arteries,  liver,  and  kidneys.  The 
treatment  is  to  withdraw  the  drug  slowly,  to  administer  alkalies 
in  large  quantity,  to  give  wholesome  food,  especially  carbohy- 
drates, and  to  place  the  patient  in  hygienic  conditions  of  living. 

Tolerance  is  but  slowly  established,  and  the  nightly  dose  may 
not  require  increasing  for  a  long  time. 

Therapeutics. — Externally,  chloral-camphor  is  employed  as  a 
counterirritant  and  local  analgesic  in  muscular  and  neuralgic  pains 
and  toothache. 

Systemically. — i.  As  a  hypnotic — in  fever,  in  various  forms 
of  delirium,  or  in  conditions  of  nervousness  or  restlessness  from 
overwork  or  excesses,  e.  g.,  alcoholic  or  sexual.  It  is  a  powerful 
and  reliable  sleep-producer  in  dose  of  10  to  30  grains  (0.7-2  gm.). 
The  beginning  dose  should  not  ordinarily  exceed  this. 

2.  As  a  circulatory  depressant — in  cases  with  high  arterial 
tension,  as  in  chronic  nephritis  or  arteriosclerosis.  Its  action 
may  be  due  to  its  effect  upon  the  viscosity  of  the  blood,  but  it  is 
probably  of  very  little  real  use.  Dose,  5  to  10  grains  (0.3-0.7  gm.) 
three  or  four  times  a  day. 

3.  In  obstetrics,  when  the  first  stage  is  prolonged,  a  dose  of 
30  grains  (2  gm.),  by  mouth  or  rectum,  may  give  the  patient  rest 
and  promote  relaxation  of  the  cervix. 

Chloral  has  some  employment  as  a  motor  depressant  in  cer- 
tain spasmodic  conditions,  such  as  whooping-cough,  chorea,  spas- 
modic asthma,  tetanus,  eclampsia,  and  strychnine-poisoning,  but 
for  an  effect  in  these  cases  larger  than  safe  doses  are  required.  It 
is  of  no  value  to  check  pain. 

Cautions  or  Contraindications. — 1.  Failure  or  threatened  fail- 
ure of  the  circulation. 

2.  Depressed  states  of  the  respiration,  as  in  pneumonia  and 
uremia. 

3.  Acute  nephritis. 

4.  Acute  gastritis  and  irritated  conditions  of  stomach. 


ETHYLATED    COMPOUNDS  343 

Administration. — In  aqueous  solution,  well  diluted,  often  with 
the  addition  of  bromides.  It  should  never  be  given  with  alcohol 
(whisky,  elixirs,  etc.),  as  the  chloral  alcoholate  formed  is  rapidly 
depressing  to  the  cerebrum  and  medulla  and  constitutes  the 
notorious  "knock-out  drops." 

Butyl  chloral  hydrate  is  sometimes  employed  for  trifacial 
neuralgia  in  dose  of  5  grains  (0.3  gm.). 

Chloralformamidum  (chloralamide)  (CCl3COH.HCONH2)  is  a 
crystalline  compound  of  chloral  and  formamide  (HCONH2), 
which  splits  into  its  components  in  the  blood.  Its  hypnotic  action, 
therefore,  results  from  chloral,  but  the  formamide  is  believed  to 
render  it  less  depressing  to  the  heart  and  vasoconstrictor  center. 
In  spite  of  the  formamide,  however,  the  chloral  set  free  has  its 
usual  metabolic  effects.  Chloralamide  is  soluble  in  18.7  parts  of 
water  and  1.3  of  alcohol.  Heated  with  water  to  6o°  C.  (i4o°F.), 
it  is  separated  into  its  components.  The  dose  for  mild  hypnosis 
is  15  to  30  grains,  administered  in  capsule,  cachet,  or  powder,  or 
in  hot  whisky.  An  elixir  is  on  the  market.  It  does  not  form 
knock-out  drops. 

Chloretone,  chlor-butanol,  or  chloroform-acetone,  CC13C- 
(CH3)2.OH,  is  a  compound  of  acetone  and  chloroform.  It  is  a 
white  powder,  soluble  in  hot  water,  alcohol,  glycerin,  and  the 
fixed  and  volatile  oils.  It  is  somewhat  antiseptic,  and  is  used  as 
a  preservative  in  solutions  of  adrenaline  and  other  unstable  bodies. 
Its  solutions  are  not  absorbed  by  the  unbroken  skin,  but  are  ab- 
sorbed by  mucous  membranes  and  raw  surfaces,  and  are  locally 
somewhat  anesthetic,  depressing  the  ends  of  the  sensory  nerves. 
On  this  account  it  may  be  used  in  solution  or  powder,  as  an  anti- 
septic, analgesic  application  to  ulcers,  as  of  the  leg  or  stomach,  or 
in  tuberculous  laryngitis  or  in  a  decayed  tooth.  In  seasickness 
it  acts  both  locally  in  the  stomach,  to  lessen  nausea  and  vomiting, 
and  as  a  central  sedative.  Systemically  it  depresses  the  cerebrum, 
producing  quiet  and  sleep.  But  it  is  a  much  less  powerful  hyp- 
notic than  chloral,  and  is  said  to  be  not  without  danger  in  the 
larger  doses.  It  has  been  recommended  for  its  narcotic  value  as 
a  preliminary  to  ether  anesthesia.    Dose,  15  grains  (1  gm.). 

In  the  laboratory  it  is  employed  to  anesthetize  small  animals, 
such  as  rabbits,  but  a  systemic  effect  sufficient  to  abolish  pain 
cannot  be  elicited  in  man  without  danger. 

ETHYLATED  COMPOUNDS 
In  experimental  chemistry  it  has  been  found  that  the  intro- 
duction of  the  radicle  ethyl,  C2H5,  into  an  organic  chemical  will 
frequently  confer  upon  it  a  sedative  action.     Hence  many  syn- 
thetic hypnotics  containing  ethyl  groups  have  been  placed  upon 


344  PHARMACOLOGY  AND  THERAPEUTICS 

the  market.  Ether  is  ethyl  oxide,  and  common  grain  alcohol  is 
ethyl  alcohol.  The  more  commonly  employed  ethylated  hyp- 
notics are: 

Sulfonal  (sulphonmethanum)  (CH3)2C.  (S02C2H5)2,  a  di-ethyl 

HsC\         .-SO2C2H5, 

compound,         /c\  and  its  tri-ethyl  congener,  trional, 

H3C         SO2C2H5 

(sulphonethylmethanum),CH3.C2H5.C(S02C2H5)2,  are  crystalline 
bodies  that  are  soluble  with  difficulty  in  water.  Trional  is  readily 
soluble  in  whisky  or  alcohol.  Dose,  15  grains  (1  gm.).  These 
drugs  are  similar  in  effects,  but  differ  in  their  rate  of  absorption 
and  their  rapidity  of  action.  Trional  is  the  more  rapidly  absorbed, 
and  being  more  highly  ethylated,  is  prompter  and  more  certain 
in  its  sedative  effects.  They  both  induce  quiet  and  sleep  without 
any  depression  of  heart  or  medullary  centers,  but  they  do  not 
allay  pain.  They  have  been  used  to  check  nausea,  as  in  seasick- 
ness, but  the  larger  doses  are  said  to  be  irritant  to  both  stomach 
and  kidneys.  They  are  eliminated  as  ethyl  sulphonates,  sulfonal 
tending  to  be  so  slowly  excreted  that  drowsiness  may  persist  the 
following  day.  They  are  usually  administered  in  capsules,  or 
with  hot  milk  or  whisky,  sulfonal  being  given  two  or  three  hours, 
and  trional  one-half  to  one  hour,  before  the  expected  sleep. 
Dreams  and  nightmares  and  herpetic  ulcers  of  the  mouth  are 
untoward  effects  attributed  to  trional. 

Poisoning  has  occurred  a  number  of  times  from  their  excessive 
use  by  the  laity,  in  amounts,  for  example,  of  200  grains  (13  gm.)  of 
sulfonal  or  1 20  grains  (8  gm.)  of  trional.  The  symptoms  are  chiefly 
gastric,  renal,  and  mental.  They  are:  nausea,  vomiting,  diarrhea, 
and  abdominal  pain,  with  stupor,  mental  confusion,  hallucina- 
tions, muscular  weakness,  and  incoordination,  followed  by  col- 
lapse and  death.  Rolleston  reports  collapse  with  unconsciousness, 
very  weak  pulse,  and  slow  breathing  from  125  grains  of  trional. 
In  some  cases,  though  not  in  all,  the  urine  contains  hematopor- 
phyrin  from  destruction  of  red  blood-cells.  It  may  contain  al- 
bumin and  casts  or  blood  from  acute  nephritis,  or  it  may  be 
suppressed.  The  poisoning  is  treated  by  large  quantities  of  milk, 
and  alkalies,  such  as  sodium  bicarbonate.  Von  Noorden  has 
advised  against  the  use  of  these  drugs  in  nephritis  because  of 
their  tendency  to  irritate  the  renal  epithelium.  Starr  mentions 
them  as  causes  of  multiple  neuritis. 

Veronal,  di-ethyl  malonyl  urea,  di-ethyl  barbituric  acid, 
C(C2H5)2.CO(CONH)2,  slightly  bitter  and  slightly  soluble  in 
water  (1  :  150),  has  an  action  resembling  that  of  trional.  It  usually 
results  in  sleep  in  one-half  to  one  hour,  and  this  lasts  several  hours. 
Veronal  may,  however,  be  very  slowly  excreted,  so  that  drow- 
siness, headache,  and  dizziness  persist  all  through  the  following 


ETHYLATED   COMPOUNDS 


345 


day.  In  some  cases  the  sleep  is  dreamy,  unrefreshing;  and  at 
times,  particularly  in  old  people,  sleep  persists  for  twenty-four 
to  thirty-six  hours.  Itching  of  the  skin,  erythema  and  other 
skin  rashes,  conjunctivitis,  and  glycosuria  have  been  reported 
following  its  use.  It  is  extensively  employed  as  a  hypnotic  in 
all  ordinary  conditions  where  sleep  is  wanting.  It  is  also  used 
to  some  extent  in  epilepsy,  delirium  tremens,  prolonged  labor, 
and  the  vomiting  of  pregnancy  and  seasickness.  Dose,  5  grains 
(0.3  gm.).  A  sodium  compound  of  veronal,  soluble  in  5  parts 
of  water,  has  been  marketed  under  the  names  Medinal  and 
Veronal-sodium.  It  is  bitter,  but  may  be  used  by  rectum,  or  even 
in  10  per  cent,  solution,  hypodermatically. 

Toxicology. — Jacobi  says  that  it  causes  relaxation  of  the 
capillary  walls  similar  to  that  from  arsenic,  with  fall  in  blood- 
pressure,  congestion  of  the  abdominal  viscera,  and  depression 
of  respiration,  in  addition  to  the  hypnotic  action.  It  does  not 
affect  the  cardiac  muscle.  The  average  lethal  dose  is  8  to  10 
gm.  The  treatment  is  for  collapse.  Several  deaths  have  been 
reported. 

Bromural,  monobrom-valeryl-urea,  (CH3)2CH.CHBr.CONH. 
CO.NH2.,  resembles  veronal  very  closely  in  its  effects  but  is  less 
active.    Dose,  15  grains  (1  gm.). 

Adalin,  brom-di-ethyl-acetyl-carbamide,  C(C2H5)2Br.CONH. 
CONH2,  is  a  substance  of  the  same  class  as  veronal  and  bro- 
mural. It  is  soluble  freely  in  alcohol,  but  with  difficulty  in 
water,  is  almost  tasteless,  and  is  milder  in  action  than  veronal. 
Dose,  15  grains  (1  gm.). 

Urethane,  aethylis  carbamas,  NH2COOC2H5,  soluble  in  less 
than  its  own  weight  of  water,  is  a  mild  hypnotic  and  diuretic  in 
dose  of  1  dram  (4  gm.).  It  changes  in  the  body  to  urea,  and 
because  of  this  fact  is  advised  against  in  nephritis. 

Hedonal  is  methyl-propyl-carbinol-urethane,  soluble  in  120 
parts  of  water  and  readily  in  alcohol.  It  is  incompatible  with 
alkalies.  Dose,  15  grains  (1  gm.).  It  has  been  used  as  an  in- 
travenous anesthetic,  Fedoroff  (1910)  reporting  330  cases.  Page 
(191 2)  recommends  a  solution  of  0.75  per  cent,  in  normal  saline 
infused  at  the  rate  of  50  to  150  c.c.  per  minute.  The  adult  dose 
is  500  c.c.  The  respiration  was  deep  and  regular,  the  pulse  good, 
the  reflexes  were  abolished.  Veale  (191 2)  employed  it  in  quan- 
tities up  to  1200  c.c,  and  from  the  larger  amounts  got  skin  edema, 
pulmonary  edema,  bronchitis,  and  pneumonia,  as  well  as  throm- 
bosis in  the  vein. 

Paraldehyd  (CH3COH)3  is  not  an  ethylated  compound,  but 
may  be  considered  here.  It  is  a  volatile  liquid  with  a  penetrating, 
disagreeable  ethereal  odor  and  a  burning  taste.    It  is  soluble  in 


346  PHARMACOLOGY  AND   THERAPEUTICS 

8  parts  of  water,  and  freely  in  alcohol  and  the  oils.  Locally  it 
resembles  ether,  and  by  its  irritation  of  the  mouth  and  probably 
also  of  the  stomach  is  a  reflex  stimulant  of  the  respiration  and 
circulation.  It  is  rapidly  absorbed,  and  soon  produces  sleep 
without  any  appreciable  depression  of  the  medullary  centers. 
The  chief  drawbacks  to  its  use  are  its  unpleasant  taste,  its  irri- 
tant local  effects,  and  the  persistence  of  its  odor  and  its  taste, 
owing  to  eructations  from  the  stomach,  or  to  its  excretion  in  the 
breath.  It  may  be  administered  dissolved  in  sweetened  water, 
syrup  of  lemon,  lemonade,  whisky,  or  beer,  which  partly  disguise 
the  taste.  It  may  also  be  given  by  rectum,  dissolved  in  water. 
Dose,  30  minims  (2  c.c.)  for  ordinary  hypnotic  effects.  In  the 
insomnia  or  delirium  of  alcoholics  it  is  sometimes  administered 
with  excellent  effect  in  doses  of  2  drams  to  y2  ounce  (8  to  15  c.c). 
We  have  seen  one  ounce  administered  in  three  hours  with  ap- 
parently nothing  but  good  effect.  Poisoning  results  in  stupor, 
with  depression  of  the  medullary  centers  and  heart  muscle,  and 
collapse.  Three  and  one-half  ounces  (100  c.c.)  at  one  dose  have 
been  recovered  from.  The  paraldehyd  habit  is  occasionally  met 
with.  Fornaca  and  QuerelK  (191 2)  record  the  case  of  a  physi- 
cian who  took  it  for  five  years,  the  nightly  dose  reaching  ]/2  ounce 
(15  c.c).  Then  symptoms  resembling  those  of  chronic  alcoholism 
were  followed  by  delirium  tremens  with  one  convulsion,  high 
temperature,  weak  pulse,  intense  sweating,  polyuria,  and  marked 
thirst. 

Recently  paraldehyd  has  been  recommended  for  intravenous 
anesthesia  by  Noel  and  Soutter  (1913).  From  5  to  15  c.c.  with 
an  equal  amount  of  ether  are  dissolved  in  150  c.c.  of  1  per  cent, 
saline,  and  injected  at  the  rate  of  about  5  to  10  c.c.  per  minute. 
A  mild  narcosis  comes  on  at  once,  and  there  is  deep  unconscious- 
ness in  one  minute.  This  ceases  soon  after  the  stoppage  of  the 
infusion.  Paraldehyd  is  detected  in  the  breath  in  ten  seconds. 
The  anesthesia  is  followed  by  easy  recovery  or  by  sleep. 

Amylene  hydrate,  dimethyl-ethyl  carbinol  (CH3)2COHC2H5 
(unofficial),  a  limpid  liquid,  soluble  in  10  parts  of  water;  resembles 
paraldehyde  in  its  action,  but  is  a  milder  hypnotic  and  less  dis- 
agreeable in  odor  and  taste.  Dose,  1  dram  (4  c.c.)  by  mouth  or 
rectum.  A  compound  of  amylene  with  chloral  is  known  as"dor- 
miol."  All  the  above  are  the  hypnotics  which  are  in  common 
use  to  induce  sleep  where  the  wakefulness  is  not  due  to  pain. 
Except  chloral  hydrate,  which  is  powerful  and  dangerous,  none 
of  these,  unless  in  doses  above  the  ordinary,  cause  any  essential 
depression  of  the  heart,  medullary  centers,  or  reflexes;  they  are, 
therefore,  safe  general  hypnotics  which  can  be  employed  even  in 
depressed  states  of  the  circulation. 


BROMIDES 


347 


Hypnotics  Which  May  Be  Used  To  Abolish  Pain 

BROMIDES 

The  bromides  in  common  use  for  narcotic  effect  are  those  of 
potassium,  sodium,  and  ammonium,  and  to  a  small  extent  those 
of  lithium,  strontium,  and  calcium.  All  have  a  strongly  salty, 
bitterish  taste,  all  are  very  soluble  in  water,  and  all  except  potas- 
sium bromide  are  moderately  soluble  in  alcohol.  The  dose  de- 
pends on  the  desired  result.  For  nervousness  and  restlessness  it 
is  10  to  20  grains  (0.7-1.3  gm.)  three  or  four  times  a  day;  as  a 
hypnotic,  20  to  60  grains  (1.3-4  gm.) ;  for  epilepsy,  20  to  60  grains 
(1.3  -4  gm.)  three  times  a  day.  L.  Pierce  Clark  reports  the  use  of 
400  grains  (27  gm.)  a  day  for  five  days  in  epilepsy.  Diluted 
hydrobromic  acid  (10  per  cent.)  is  sometimes  used  as  a  bromide 
in  dose  of  1  dram  (4  c.c).  In  equivalent  sedative  dose  it  has  no 
advantage  over  the  alkaline  bromides,  and  is  strongly  acid. 

Pharmacology. — Local. — Bromides  have  no  effect  upon  the 
unbroken  skin;  but  on  mucous  membranes  and  raw  tissues  they 
have  a  salt  action,  and  are  irritant  unless  well  diluted.  From 
irritation  of  the  stomach  they  sometimes  cause  nausea  and  vomit- 
ing. Before  the  use  of  cocaine  their  solutions  were  painted  on  the 
throat  as  mild  anesthetics  to  favor  laryngeal  examination. 

Absorption  is  fairly  rapid  from  stomach  and  intestines. 

Nervous  System. — On  the  whole  nervous  system  except  the 
medulla  there  is  a  moderate  but  lasting  general  depression  which 
can  be  maintained  day  after  day  for  long  periods,  with  little,  if 
any,  effect  upon  the  vital  medullary  centers. 

Cerebrum. — The  mind  is  less  alert,  the  special  senses  are  less 
keen,  the  sense  of  pain  is  diminished,  and  there  is  indifference  or 
lack  of  attention  to  what  is  going  on.  Large  doses  produce  drowsi- 
ness, and  if  the  dose  is  given  at  bedtime,  favor  the  onset  and 
maintenance  of  sleep;  but  even  enormous  doses  (400  grains  a 
day)  will  not  force  sleep  in  the  daytime,  when  the  patient  is  up 
and  about.  As  a  hypnotic,  the  drug  acts  rather  to  permit  sleep, 
as  when  the  patient  is  anxious,  worried,  or  nervous,  than  to  force 
it  by  marked  depression  of  the  cerebrum. 

From  repeated  very  large  doses,  as  sometimes  used  in  epilepsy, 
the  patient  passes  into  a  condition  of  mental  and  physical  slug- 
gishness, with  defective  memory,  stupidity,  general  apathy,  and 
inferior  mental  power. 

The  motor  areas  of  the  cortex  are  depressed,  for  in  a  dog 
under  bromides  it  is  impossible  to  produce  a  convulsion  by  their 
stimulation.  In  man,  too,  voluntary  motion  is  sluggish,  and  the 
cerebral  convulsions  of  epilepsy  may  be  absolutely  prevented. 
These  cerebral  effects  are  directly  opposed  by  caffeine. 


348  PHARMACOLOGY  AND  THERAPEUTICS 

Upon  the  cord  the  effect  is  the  opposite  to  that  of  strychnine, 
the  passage  of  impulses  from  afferent  fibers  to  motor  areas  being 
retarded,  and  there  is  some  evidence  that  it  acts  on  the  same 
part  of  the  cord  as  strychnine,  i.e.,  the  primary  sensory  synapses. 
It  is,  therefore,  irrational  to  administer  bromides  and  strychnine 
together.  If  a  large  dose  of  strychnine  is  given  to  a  bromidized 
dog,  a  reflex  response  to  a  stimulus  may  be  obtained,  but  the 
extensive  convulsive  response  which  would  result  from  the  strych- 
nine alone  does  not  occur.  The  depression  of  the  reflexes  makes 
a  general  depression  of  muscular  tone  throughout  the  body,  and 
loss  or  depression  of  the  sexual  reflex,  but  not  usually  the  bladder 
reflex. 

Circulation. — Under  ordinary  conditions  there  is  no  essential 
effect  from  therapeutic  doses  upon  the  heart,  the  arteries,  or  the 
nervous  mechanisms  of  control.  But  in  the  cardiac  neuroses, 
palpitation,  tachycardia,  etc.,  and  when  the  heart  is  overacting, 
as  from  general  nervousness,  the  effect  of  a  bromide  may  be  to 
steady  and  quiet  the  beat  by  its  general  sedative  effect  upon  the 
patient.  By  enormous  doses  the  muscles  of  the  heart  and  arteries 
and  the  vasoconstrictor  center  are  depressed  and  arterial  pressure 
falls.  In  large  amounts  the  potassium  ion  is  distinctly  depressing 
to  the  heart  muscle;  hence  potassium  bromide  in  the  large  doses 
tends  to  be  more  depressing  than  the  other  salts. 

Respiratory. — Therapeutic  doses  have  no  effect  except  to 
diminish  the  coughing  reflex  and  lessen  the  tone  of  the  respiratory 
muscles.    Enormous  doses  somewhat  depress  the  center. 

Sexual  Organs. — Both  sexual  desire  and  sexual  power  are  di- 
minished through  cerebral  and  spinal  depression,  and  these 
effects  are  made  use  of  in  therapeutics. 

Elimination. — Bromides  are  excreted  chiefly  in  the  urine,  but 
somewhat  also  in  the  sweat,  in  mucous  secretions,  and  in  milk. 
Large  doses  given  to  a  nursing  mother  may  affect  the  infant.  The 
excretion  begins  very  quickly,  traces  being  found  in  the  urine  and 
saliva  in  a  few  minutes  after  ingestion.  But  a  part  of  the  bromide 
enters  the  body  fluids  and  protoplasm  and  replaces  some  of  the 
normal  sodium  chloride,  and  this  portion  is  but  slowly  excreted, 
so  that  bromide  may  be  found  in  the  urine  weeks  after  its  admin- 
istration has  been  stopped.  The  excretion  of  bromides  is  hastened 
by  large  doses  of  sodium  chloride;  so  in  extreme  bromide  admin- 
istration, as  in  some  epileptic  cases,  the  amount  of  chlorides  is 
reduced,  the  bromide  being  taken  with  the  food  in  the  place  of 
table  salt  (sodium  chloride) .  Where  much  bromide  is  given  con- 
tinually, hydrobromic  acid  is  said  to  replace  some  of  the  hydro- 
chloric acid  of  the  gastric  juice. 

Skin  and  Mucous  Membranes. — Scattered  acne  pustules  very 


Fig.  37. — Bromide  eruption  (Schamberg). 


Fig.  38.— Pustulobullous  eruption,  resembling  small-pox,  from  the  ingestion  of 
bromides  (Schamberg). 


M 


sa 


BROMIDES  349 

frequently  appear  on  the  face,  chest,  and  back;  more  rarely  the 
eruption  may  be  erythematous,  urticarial,  furuncular,  or  bullous. 
In  some  cases  extensive  superficial  ulceration  has  caused  serious 
symptoms.  Bromide  eruptions  have  been  mistaken  for  tertiary 
syphilitic  manifestations.  The  etiology  of  these  rashes  is  a  matter 
of  some  controversy.  It  has  been  suggested  that  the  gland  mouths 
are  irritated  by  an  accumulation  of  the  excreted  salt  as  the  sweat 
evaporates;  also  that  the  acid  of  the  sebaceous  secretion  de- 
composes the  bromide  and  sets  free  the  irritating  bromide.  But 
irritation  occurs  in  mucous  membranes  where  the  secretion  is 
alkaline,  and  no  excess  of  bromide  and  no  free  bromine  have  been 
found  in  washings  from  the  skin,  or  in  the  sweat  or  sebaceous 
secretions,  and  though  the  drug  is  reported  to  have  been  found 
a  few  times  in  the  sebaceous  glands,  most  investigators  have  not 
found  any  there  at  all.  But  better  evidence  than  any  other  that 
the  rash  is  not  due  to  gland  irritation  is  the  observation,  by  a 
number  of  careful  dermatopathologists  (Thin,  Colcott  Fox,  Harris, 
etc.),  that  the  changes  begin  in  the  papillary  layer  and  not  neces- 
sarily in  or  about  the  glands,  though  the  glands  may  be  involved 
secondarily. 

It  has  been  claimed  that  in  chronic  nephritis,  on  account  of 
obstruction  of  the  regular  channel  of  elimination,  the  rashes  are 
more  severe.  But  rashes  are  too  frequent  in  those  with  normal 
kidneys  to  allow  us  to  consider  diseased  kidneys  of  any  great  im- 
portance as  an  etiologic  factor,  though  they  may  have  to  do  with 
the  severity  of  the  dermal  reaction.  L.  Pierce  Clark  reports 
that  even  after  enormous  dosage  he  has  been  able  to  prevent  the 
eruption  by  daily  colon  irrigations.  That  the  nervous  system  is 
a  factor  is  held  by  some,  on  the  grounds  that  very  small  amounts 
are  sufficient  to  produce  a  rash  in  those  who  show  the  idiosyn- 
crasy, and  that  sometimes  in  these  same  persons  the  larger  doses 
produce  the  least  rash;  in  addition  most  of  these  rashes  are  ac- 
companied by  vasomotor  disturbances.  On  the  theory  that  it 
is  due  to  the  elimination  of  toxic  products,  colon  irrigations  have 
been  advised,  also  large  doses  of  alkalies,  intestinal  antiseptics, 
arsenic,  and  potassium  bitartrate,  and  in  addition  special  clean- 
liness of  the  skin.  The  rash  of  the  face,  for  example,  is  said  to  be 
lessened  by  vigorous  washing.  Stelwagon  suggests  diuretics  and 
the  free  drinking  of  water,  or,  in  other  words,  the  promotion  of 
rapid  elimination.  He  states  that  sodium  bromide  is  less  likely 
to  produce  a  rash  than  the  potassium  salt. 

Kidneys. — There  is  no  special  effect  upon  the  kidneys,  except 
that  large  doses  with  plenty  of  water  act  like  other  diffusible 
salts  to  increase  the  excretion  of  urine. 

Toxicology. — Acute  poisoning  from  a  single  very  large  dose 


350  PHARMACOLOGY  AND   THERAPEUTICS 

shows  in  profound  depression  and  apathy,  or  an  actual  stupor 
lasting  from  one  to  several  days,  with  slow  respiration  and  rather 
low  arterial  pressure.  Death  has  rarely,  if  ever,  resulted  from 
bromide  alone. 

Chronic  Poisoning  or  Bromism. — Following  repeated  large 
doses  of  bromide  the  patient  becomes  dull,  stupid,  indifferent,  the 
face  expressionless,  pale,  usually  bearing  scattered  pimples,  the 
eyes  heavy,  all  mental  processes  and  voluntary  movements  slug- 
gish (speaking  is  slow,  replies  to  questions  are  delayed,  walking 
is  deliberate),  the  memory  defective,  general  tone  less,  sexual 
desire  and  sexual  power  abolished,  and  there  are  loss  of  appetite, 
nausea,  constipation,  and  a  general  lowering  of  vitality  and  vigor. 
This  is  the  state  into  which  some  epileptics  are  brought  by  ex- 
cessive bromide  treatment;  and  it  is  nowadays  thought  better, 
except  in  refractory  cases,  to  take  some  risk  of  convulsions  rather 
than  to  bring  a  patient  into  such  a  hopeless  condition  of  useless- 
ness.    Many  epileptics  have  led  active  lives,  e.  g.,  Napoleon  I. 

Treatment  for  Acute  and  Chronic  Poisoning. — Stop  the  drug, 
give  sodium  chloride  and  much  water  to  favor  elimination,  keep 
up  body  activity  as  far  as  possible,  and  body  nutrition,  and  coun- 
teract the  central  depression  with  strychnine  and  caffeine. 

Therapeutics. — Bromides  have  their  chief  employment  as 
sedatives  in  hyperesthetic  states  of  the  nervous  system.  They 
may  also  be  employed  to  promote  sleep,  especially  when  wake- 
fulness is  due  to  worry  or  excitement  or  to  moderate  pain,  as  in 
toothache  or  neuralgia. 

Some  of  their  every-day  uses  are: 

i.  To  lessen  nervous  irritability,  as  in  general  restlessness,  in 
exophthalmic  goiter,  and  in  the  gastric,  intestinal,  and  cardiac 
neuroses. 

2.  To  allay  pain  (as  of  neuralgia,  neuritis,  toothache,  etc., 
which  is  felt  keenly  because  of  a  hyperesthetic  nervous  state). 

j.  To  check  vomiting  if  reflex  or  central,  as  in  seasickness,  and 
not  from  stomach  irritation.  It  is  sometimes  employed  in  the 
vomiting  of  pregnancy. 

4.  To  lessen  sexual  hyperesthesia,  as  in  nymphomania  and 
chordee,  and  following  operations  upon  the  penis  in  the  adult, 
as  circumcision. 

5.  To  prevent  convulsions,  as  those  of  epilepsy,  tetanus,  and 
strychnine  poisoning.  For  the  last,  doses  of  not  less  than  half  an 
ounce  by  mouth  or  rectum  may  be  employed.  It  acts  rather 
slowly. 

6.  To  check  spasmodic  nervous  afections  of  striated  muscle, 
such  as  chorea,  whooping-cough,  persistent  hiccup,  laryngismus 
stridulus,  and  convulsive  tic. 


OPIUM  351 

7.  To  quiet  the  reflexes  (lessen  the  heightened  tone)  in  spastic 
conditions  due  to  lesions  of  the  motor  tract,  as  in  multiple  sclerosis. 

8.  To  lessen  cardiac  excitability,  as  in  extrasystoles  and  par- 
oxysmal tachycardia — doses  of  2  to  3  drams  (8-12  gm.). 

Of  the  various  bromides,  the  potassium  and  sodium  salts,  in 
ordinary  doses,  have  no  measurable  differences,  and  are  preferred 
to  the  others.  In  the  very  large  doses  the  potassium  radicle  may 
have  a  special  depressing  effect  upon  the  muscle  of  the  heart  and 
arteries.  The  belief  that  ammonium  bromide  is  less  depressing 
to  the  heart  than  the  other  bromides  is  not  justified.  (See  Am- 
monium Chloride.) 

Bromipin  is  a  combination  of  bromine  with  oil  of  sesame,  and 
may  be  given  in  the  form  of  an  emulsion.  It  is  said  to  be  free 
from  irritating  effects  upon  the  stomach,  and  is  sometimes  sub- 
stituted for  the  alkaline  bromides  when  there  is  gastric  irritability. 
It  is  of  two  strengths,  10  and  25  per  cent.,  and  the  dose  is  1  to  2 
drams  (4-8  c.c.)  made  into  an  emulsion.  In  epilepsy  Kothe  recom- 
mends 75  grains  (5  gm.)  three  times  a  day,  increasing  up  to  600 
grains  (40  gm.). 

Bromoform  (CHBr3)  is  a  homologue  of  chloroform,  CHC13. 
It  is  a  heavy  liquid,  readily  soluble  in  alcohol,  very  slightly  soluble 
in  water,  and  sweet  to  the  taste.  It  is  very  limpid,  so  that  1  minim 
contains  about  5  or  6  drops.  Its  only  therapeutic  use  is  in  the 
treatment  of  whooping-cough.  The  dose,  3  drops,  or  y2  minim 
(0.03  c.c.)  for  a  child  one  year  old,  or  5  minims  (0.3  c.c.)  for  an 
adult,  is  usually  given  suspended  in  syrup,  but  is  better  dissolved 
in  alcohol  or  oil.  Poisoning  has  occurred  a  number  of  times  from 
the  undissolved  bromoform  at  the  bottom  of  a  bottle,  so  it  should 
be  well  shaken  before  the  dose  is  poured  out.  Serious  narcosis 
and  collapse  are  reported  in  a  child  of  eighteen  months  from  a 
dose  of  8  drops. 

OPIUM 

Opium  is  the  "concrete  milky  exudation  obtained  by  incising 
the  unripe  capsules  of  Papaver  somniferum  (Fam.  Pa  paver  acece), 
and  yielding,  in  its  normal  moist  condition,  not  less  than  9  per 
cent,  of  morphine."  It  is  simply  the  dried  milk- juice  which 
exudes  from  two  or  three  encircling  incisions  made  in  the  green 
poppy  capsules  of  the  common  poppy  as  grown  in  oriental  coun- 
tries. The  only  opium  that  meets  the  U.  S.  P.  requirements  is 
that  from  Asia  Minor,  known  as  Turkish  or  Smyrna  opium.  That 
used  for  smoking  is  less  strong  and  comes  mostly  from  India  and 
China. 

Opium  is  expensive  and  is  much  adulterated  with  vegetable 
debris,  sand,  earth,  and  even  nails  and  bullets  to  increase  its 


352  PHARMACOLOGY  AND  THERAPEUTICS 

weight.  It  is  of  a  gummy  consistence  from  much  moisture;  but 
when  the  moisture  is  driven  off  by  heat,  it  can  be  powdered  or 
granulated.  The  dried  opium  is  stronger  by  the  amount  of  water 
driven  off.  For  the  manufacture  of  all  the  official  preparations 
the  Pharmacopoeia  employs  dried  opium  in  the  form  of  powdered 
opium  (opii  pulvis),  or  granulated  opium  (opium  granulatum), 
and  these  are  required  by  the  Pharmacopoeia  to  assay  from  12 
to  12.5  per  cent,  of  morphine. 

The  opium  alkaloids  are  about  19  in  number,  and  form  a 
closely  related  series,  at  one  end  of  which  stands  morphine,  with  its 
dominant  property,  the  narcotic  one,  but  with  some  tendency  to 
stimulate  the  reflexes,  and  at  the  other  end  thebaine,  with  no 
narcotic  power,  but  a  typical  strychnine  action  upon  the  cord. 
On  account  of  these  other  substances,  therefore,  opium  may  be 
less  sedative  than  morphine.  None  of  these  alkaloids  are  isolated 
and  used  except  morphine  and  codeine. 

Besides  the  12  to  12.5  per  cent,  of  morphine,  the  dried  opium 
contains  0.5  to  1  per  cent,  of  codeine,  5  or  6  per  cent,  of  narcotine 
(a  nauseating  principle),  and  15  or  more  other  alkaloids  in  small 
amounts.  It  contains  neither  starch  nor  tannic  acid,  and  the 
presence  of  these  would  indicate  adulteration. 

Preparations  and  Doses. — These  are  made  from  powdered 
opium  (opii  pulvis)  or  granulated  opium  (opium  granulatum), 
containing  12  to  12.5  per  cent,  of  morphine;  dose,  1  grain  (0.06 
gm.),  which  contains  f  grain  (0.008  gm.)  of  morphine. 

Solids — Deodorized    opium — of    same    strength    as    powdered 

opium,  but  with  the  narcotine  and  certain  disagreeable 

odorous  substances  removed  by  benzin. 

Extract,  containing  20  per  cent,  morphine.     It  is  an  aqueous 

extract,  therefore  contains  only  those  parts  of  the  opium 

which  are  soluble  in  water.    Dose,  Ya  grain  (0.045  gm-)- 

Pill,  containing  powdered  opium,  1  grain  (0.06  gm.). 

Powder  of  ipecac  and  opium  (Dover's  powder),  10  per  cent. 

of  each.    Dose,  10  grains  (0.07  gm.). 
Troches  of  licorice  and  opium  (Wistar's  lozenge),  each  contain- 
ing powdered  opium,  -^  grain  (0.005  gm-)- 
Plaster — 6  per  cent,  of  extract. 
Liquids — Tincture  (laudanum),  10  per  cent. 
Deodorized  tincture,  10  per  cent. 
Tincture  of  ipecac  and  opium,  of  each,  10  per  cent. 
Vinegar,  10  per  cent. 
Wine,  10  per  cent. 
Dose  of  each,   10  minims  (0.7  c.c.)    containing  ^  grain  of 
morphine. 
Camphorated  tincture   (paregoric),  4:  1000.     Dose,  1   dram 


OPIUM 


353 


(4  c.c.)  =  opium,  yA  grain  (0.015  gm.)  =  morphine,  ¥V  grain 
(0.002  gm.). 
Lead  and  Opium  Wash  (Lotio  Plumbi  et  Opii,  N.  F.)  is  made 
by  adding  the  tincture  of  opium,  %  dram  (15  c.c.),  to  a 
solution  of  lead  acetate,  2  drams  (8  gm.),  in  water  sufficient 
to  make  the  total  measure  one  pint.     It  is  an  irrational 
mixture,  as  the  opium  principles  are  not  absorbed;  its 
action  is  that  of  lead  acetate. 
Some  of  the  alkaloids  or  their  salts  are  also  employed,  viz. : 
Codeine — soluble  in  88  parts  of  water  and  in  1.6  of  alcohol;  codeine 
phosphate,  soluble  in  2.5  of  water  and  261  of  alcohol;  codeine 
sulphate,  soluble  in  30  of  water  and  1035  of  alcohol.    The  pure 
alkaloid  is  best  for  use  in  alcoholic  solution,  and  the  phos- 
phate for  aqueous  solution,  as  in  hypodermic  administration. 
Dose,  y2  grain  (0.03  gm.). 
Morphine  and  morphine  acetate — not  readily  soluble  in  water; 
morphine  chloride,  soluble  in  17.2  of  water  and  42  of  alcohol; 
and  morphine  sidphate,  soluble  in  15.3  of  water  and  465 
of  alcohol.    One  grain  of  morphine  sulphate  is  equivalent 
to  about  2<4   grain  of  pure  morphine.    Dose,   y^  grain 
(0.015  gm-)- 
Compound  morphine  powder  (Tully  powder)  contains  1.5  per 
cent,  of  morphine  sulphate,  with  camphor,  licorice,  and 
chalk.     Dose,  10  grains    (0.7  gm.),  containing   about   7- 
grain  (0.009  gm-)  °f  morphine  sulphate. 
Magendie's  solution  is  unofficial,  but  is  much  employed  in 
hospitals.    It  has  a  strength  of   1:30,  i.  e.,  5  minims  =  ^ 
grain  of  morphine  sulphate.     It  slowly  weakens  and  ac- 
quires a  brown  color,  owing  to  the  formation  of  oxydi- 
morphine. 
Pantopon  is  a  preparation  purporting  to  be  composed  of  the 
alkaloids  of  opium  in  the  same  proportion  as  in  opium 
itself.    Dose,  twice  that  of  morphine. 
Pleistopon  is  a  similar  preparation  with  the  narcotine  re- 
moved. 
Pharmacologic  Action. — Local. — Morphine  has  no  local  action. 
Its  control  over  pain  is  purely  central,  therefore  it  acts  only  after 
absorption.  Thus,  because  it  must  be  absorbed  and  must  reach  the 
centers  before  it  can  lessen  pain,  morphine  or  opium  applied  to  a 
painful  spot  has  no  more  power  to  relieve  pain  at  that  spot  than 
a  dose  given  by  mouth;  and,  after  local  application,  pain  is  re- 
lieved in  distant  parts  of  the  body  as  readily  as  at  the  site  of 
application.     Hence  the  use  of  morphine  or  opium  in  dusting- 
powder,  suppository,  or  ointment  is  irrational,  is  without  advan- 
tage, and  has  the  disadvantage  of  uncertainty  of  absorption. 
23 


354  PHARMACOLOGY  AND   THERAPEUTICS 

Stomach. — No  local  action.  Through  its  central  action  it 
tends  to  lessen  motor  activity  and  to  retard  the  secretion  of 
gastric  juice.  Riegel,  also  Hirsch,  asserts  that  after  a  temporary 
diminution  the  secretion  increases  to  beyond  the  normal. 

The  motor  functions  are  decidedly  retarded.  Hirsch  (iqoi) 
noted  a  tonic  spasm  of  the  pyloric  sphincter,  and  this  has  been 
confirmed  by  the  #-ray  observations  of  Magnus  (1907)  on  cats. 
Instead  of  two  or  three  hours  for  the  stomach  to  empty  itself,  a 
hypodermic  of  %  grain  (0.01  gm.)  made  the  emptying  time 
eight  to  twelve  or  even  twenty-four  hours.  The  food  is  so  much 
more  digested  than  normally  that  it  promotes  constipation. 

Our  chief  concern  as  regards  the  stomach  is  the  undesirable 
after-effect  of  nausea  and  vomiting.  To  what  these  are  due  is 
not  positively  known.  A  dog  regularly  vomits  a  few  minutes 
after  a  dose  of  morphine, — even  a  minute  dose,  as  0.0001  gm.  per 
kilo, — whether  given  by  mouth  or  hypodermatically ;  but  in  man 
there  is  no  nausea  for  several  hours.  That  the  effects  are  not  due, 
at  least  in  man,  to  excretion  of  morphine  itself  is  indicated  by  the 
fact  that  doses  administered  by  mouth  have  no  especially  nauseat- 
ing effect  before  absorption,  and  by  Alt's  finding  that  after  a 
hypodermic  injection  morphine  appeared  in  the  saliva  in  two 
and  one-half  minutes,  and  in  the  gastric  secretions  in  three  min- 
utes, and  had  disappeared  from  the  stomach  in  an  hour — long 
before  the  nausea  developed.  It  would  seem  to  be  due,  therefore, 
in  man,  to  the  formation  from  the  morphine,  of  some  substance 
with  an  apomorphine  effect  upon  the  vomiting  center.  In  spite 
of  this  nauseating  tendency  morphine,  because  of  its  central  seda- 
tive action,  will  prevent  the  production  of  vomiting  by  irritants 
in  the  stomach.  The  narcotine  in  opium  is  said  to  make  it  more 
nauseating  than  morphine. 

Magnus  noted  that  under  morphine  a  stomach  tends  to  dilate 
and  to  lose  its  muscular  tone ;  the  morphine  given  post-operative 
may  be  a  cause  of  acute  dilatation  of  the  stomach. 

Intestines. — Morphine  diminishes  both  secretion  and  peristal- 
sis, but  particularly  the  latter;  and  so  powerful  is  it  that  it  is 
regularly  employed  in  peritonitis,  or  after  operations  where  it  is 
essential  to  keep  the  intestines  quiet.  Because  of  this  ability  to 
keep  the  bowel  immovable  it  is  sometimes  called  the  "bowel 
splint."  It  acts  when  the  intestine  is  severed  from  the  central 
nervous  system,  and  apparently  by  depressing  the  nerve  centers 
in  the  intestinal  walls  (Auerbach's  plexus).  After  morphine  even 
local  irritants  of  the  intestines  do  not  induce  peristalsis.  This 
morphine  constipation  is  often  very  undesirable  and  a  great  draw- 
back to  the  use  of  morphine.  Factors  which  perhaps  contribute 
to  the  constipation  are:    (1)   The  stomach  retention,  which  not 


OPIUil 


355 


only  causes  delay  in  the  passage  of  food,  but  permits  such  in- 
creased digestion  as  to  lessen  the  food  residue,  which  is  a  normal 
intestinal  stimulant;  (2)  weakening  of  the  irritability  of  the 
vagus  endings  and  splanchnic  (inhibitory)  stimulation,  and 
(3)  possibly  a  closure  of  the  ileocolic  valve  similar  to  that  of 
the  pylorus. 

Large  doses  occasionally  result  in  diarrhea,  and  this  effect 
may  be  analogous  in  its  etiology  with  the  nausea,  i.  e.,  central  or 
due  to  the  formation  of  an  irritant  substance.  Sometimes  in 
painful  chronic  disease  requiring  much  morphine  a  long-standing 
constipation  will  suddenly  change  to  an  intractable  diarrhea,  and 
this  may  be  a  terminal  condition,  death  following  in  three  or  four 
days.  In  some  cases,  too,  where  constipation  results  from  colicky 
spasms,  a  dose  of  morphine,  by  allaying  irritation  and  allowing 
peristalsis  to  go  on,  may  cause  the  bowels  to  move.  In  colic  or 
pain  due  to  an  irremovable  source  of  irritation,  e.  g.,  adhesions, 
morphine  may  be  required  to  allay  the  pain;  but  it  should  never 
be  employed  until  all  doubt  as  to  the  immediate  necessity  of 
surgical  interference  is  settled.  Many  deaths  have  resulted  owing 
to  the  postponement  of  operation,  because  of  the  masking  of  the 
symptoms  by  morphine. 

Absorption. — Morphine  is  absorbed  very  rapidly  through  mu- 
cous membranes,  and  slowly,  if  at  all,  through  the  unbroken  skin. 
When  opium  is  used,  the  extractive  matters  retard  the  absorption 
of  the  alkaloids. 

Circulation. — The  direct  effect  upon  heart  and  arteries  is  prac- 
tically none.  (Sollmann  says  slight  stimulation  of  cardiac  muscle.) 
There  is  some  stimulation  of  the  vasoconstrictor  center  and  a 
noticeable  stimulation  of  the  vagus  center,  the  heart,  after  a  large 
dose,  being  slowed  even  to  the  extent  or  10  or  20  beats  per  minute 
without  change  in  arterial  pressure.  An  element  in  the  slowing 
may  also  be  the  quiet  induced.  In  addition  the  cutaneous  arteri- 
oles may  be  dilated,  with  flushing  of  the  skin.  In  poisoning  by 
morphine  the  heart  frequently  remains  strong  until  near  death, 
so  that  more  vigorous  restorative  measures  may  be  adopted  than 
in  poisoning  by  other  narcotics. 

Respiration. — In  the  use  of  morphine  in  severe  diseases  the 
depression  of  the  respiration  is  a  serious  drawback.  A  resting 
rabbit,  expiring  200  c.c.  of  air  in  thirty  seconds,  was  given  % 
grain  (0.01  gm.)  of  morphine  (a  heavy  dose),  and  the  air  expired 
fell  to  90  c.c.  in  the  same  time.  Though  the  individual  respira- 
tions were  deeper,  the  breathing  was  greatly  slowed.  In  poisoning 
in  man  the  respiration  becomes  very  slow, — even  down  to  three 
or  four  per  minute, — the  individual  inspirations  being  deep  at 


356  PHARMACOLOGY  AND  THERAPEUTICS 

first  but  eventually  shallow.  The  breathing  is  not  infrequently 
of  the  Cheyne-Stokes  type. 

Relation  to  Carbon  Dioxide. — In  normal  sleep,  or  in  the  sleep 
following  the  ordinary  hypnotic  dose  of  chloral  or  sulfonal,  the 
breathing  is  slowed  because  of  the  lessened  need  of  the  inactive 
body  for  oxygen,  but  there  is  no  change  in  the  percentage  of  car- 
bon dioxide  in  the  blood.  But  in  morphine  narcosis,  and  even 
after  quite  small  doses  of  morphine,  the  breathing  is  reduced  be- 
low the  requirements  of  the  body,  and  the  blood  is  found  to 
contain  a  percentage  of  CO2  above  the  normal. 

Experiments  show  that  when  the  respiratory  center  loses  its 
sensitiveness,  a  greater  than  normal  percentage  of  CO2  in  the 
blood  is  required  to  bring  about  respiration;  and  that  slow 
breathing,  or  even  Cheyne-Stokes  breathing,  may  be  the  result 


Fig.  41. — Record  showing  typical  Cheyne-Stokes  respiration  (from  a  case  of 
aortic  and  mitral  insufficiency  with  arteriosclerosis).  The  time  record  gives 
seconds  (Howell). 


of  a  diminished  sensitiveness  of  the  respiratory  center.  Cheyne- 
Stokes  respiration  consists  of  alternating  periods  of  apnea  and 
hyperpnea,  and  indicates  depression  of  the  respiration.  In  it 
there  must  be  a  larger  than  normal  percentage  of  C02  in  the 
blood  or  the  center  is  not  stimulated  to  activity.  During  the 
pauses  of  apnea  the.  C02  accumulates,  and  during  the  active 
breathing  C02  is  given  off  until  a  state  of  acapnia  and  overoxy- 
genation  results.  However,  the  amount  of  oxygen  available 
makes  no  difference,  for  it  is  not  a  question  of  the  amount  of 
oxygen  in  the  blood,  but  of  the  amount  of  C02.  Indeed,  the 
depression  of  respiration  may  be  overcome  by  the  inhalation  of 
COo  (Leonard  Hill). 

In  this  we  rind  an  explanation  of  the  depression  of  respiration 


opium  357 

and  the  Cheyne-Stokes  breathing  of  morphine;  viz.,  a  lessened 
sensitiveness  of  the  respiratory  center  to  stimulation  by  C02.  The 
center  is  still  subject  to  reflex  stimulation,  for  a  sudden  arousing 
of  the  patient  is  accompanied  by  improved  breathing  for  a  time, 
and  a  dash  of  cold  water,  even  in  coma,  may  induce  several  deep 
respirations. 

Cough  is  also  overcome,  the  central  depression  lessening  the 
reflex  from  mucus  or  from  an  area  of  irritation  in  the  respiratory 
tract.  This  effect  on  cough  is  a  highly  valuable  one  in  therapeu- 
tics, but  it  is  undesirable  or  even  dangerous  when  there  is  an  ex- 
cessive production  of  mucus  or  exudate  which  should  be  coughed 
out. 

The  bronchial  secretions  are  somewhat  decreased,  but  this  is 
not  an  important  property  in  therapeutics. 

Nervous  System. — A  therapeutic  dose  of  morphine  lengthens 
the  reaction  time  to  stimuli,  lessens  the  sensitiveness  to  pain  and 
other  disturbing  factors,  and  promotes  a  dreamy,  abstracted  state 
of  the  mind;  or  it  induces  sleep.  These  effects  occur  without  any 
essential  muscular  relaxation  or  circulatory  depression.  That 
the  senses  are  less  keen  has  been  shown  in  the  case  of  touch  by 
the  esthesiometer,  in  the  case  of  sight  by  special  apparatus,  in 
the  case  of  pain  by  vast  clinical  experience.  That  mental  activity 
is  lessened  is  demonstrated  by  the  increased  time  required  to 
add  a  column  of  figures  or  to  answer  questions;  but  there  is  never 
such  depression  of  the  intellect  as  from  alcohol.  Morphine  acts 
chiefly  by  dulling  the  perceptions.  It  is  noteworthy  that  slight 
stimuli,  such  as  ordinary  pinching  or  noises,  or  steady  contin- 
uous stimuli,  like  continuous  pain  (unless  very  severe),  are  un- 
appreciated after  a  moderate  dose  of  morphine  and  do  not  prevent 
sleep;  yet  a  sudden  strong  stimulus,  such  as  a  flash  of  lightning  or 
the  deep  prick  of  a  pin,  may  arouse  one  almost  as  promptly  as 
usual,  unless  a  large  dose  has  been  taken. 

Morphine  has  the  power,  above  all  other  drugs,  to  overcome 
pain  and  to  compel  sleep,  in  spite  of  everything  which  ordinarily 
tends  to  keep  the  patient  awake.  But  in  the  presence  of  very 
severe  pain  sleep  from  large  doses  may  not  be  any  deeper  or 
more  prolonged  than,  without  pain,  it  would  be  from  a  much 
smaller  dose.  Unfortunately,  morphine  has  undesirable  side- 
effects,  and  in  some  chronic  cases  with  severe  pain  these  prevent 
the  administration  of  sufficient  quantities  to  give  ease  to  the 
patient. 

Morphine  stands  by  itself  in  its  power  to  allay  pain,  to  lessen 
anxiety  and  nervous  fear,  and  to  change  discomfort  into  comfort. 
In  chronic  incurable  diseases  it  may,  even  in  doses  as  small  as 


358  PHARMACOLOGY   AND   THERAPEUTICS 

^o~i2  grain  (0.003-0.005  gm.),  dull  the  perceptions,  promote 
ease  of  mind,  and  prevent  worry  and  physical  distress. 

Ordinarily  after  a  dose  of  morphine  there  is  no  appreciable 
period  of  exhilaration;  but  in  the  habitue,  as  the  dreamy  condi- 
tion comes  on,  the  emotional,  imaginative,  and  animal  tendencies 
are  set  free  to  some  extent  before  sleep  supervenes.  This  suggests 
the  alcohol  effect,  but  the  narcosis  of  morphine  differs  from  that 
of  alcohol  in  that  there  is  not  the  great  depression  of  the  intellec- 
tual and  motor  powers.  For  when  a  morphine  patient  is  aroused 
he  can  reply  to  questions  rationally,  i.  e.,  with  the  intelligence 
that  any  one  might  show  on  being  aroused  from  a  deep  sleep, 
and  he  can  speak  clearly  and  can  use  his  limbs,  though  he  relapses 
promptly  into  sleep  on  being  left  alone.  There  is  no  effect  from 
morphine  that  corresponds  with  the  stupidity  and  muscular  re- 
laxation of  a  drunken  man.  A  morphine  patient  always  brightens 
up  on  being  aroused,  and  his  breathing  improves,  so  that  from  a 
person  who  looks  dangerously  depressed  and  "doped, "  he  changes 
to  one  that  can  smile  and  reply  to  questions.  If  allowed,  he 
promptly  relapses  into  sleep,  but  the  sleep  is  at  first  light,  and  it 
is  some  time  before  he  again  reaches  the  stage  of  deep  depression. 
In  cats  and  some  human  beings,  mostly  women,  cerebral  stimula- 
tion and  excitement  regularly  result  instead  of  depression. 

Motor  Areas. — The  motor  area  of  the  cortex  is  not  found  to 
have  lost  its  excitability  to  any  great  extent,  as  after  chloral  or 
bromide,  so  that  a  dog  will  die  from  respiratory  depression  before 
there  is  lessened  response  to  electric  stimulation  (Hitzig  and 
others).  But  voluntary  muscular  activity  is  sluggish  because  of 
the  diminished  perception  of  stimuli  and  the  sluggishness  of  cere- 
bral activity.  There  may  be  some  incoordination,  and  this  is 
attributed  to  depression  of  the  cerebellum. 

Spinal  Cord. — In  some  of  the  lower  mammals,  e.  g.,  the  cat, 
there  is  increased  activity  of  the  reflexes,  and  there  may  be  con- 
vulsions of  the  typical  strychnine  type.  In  man,  however,  there 
is  probably  moderate  depression  of  the  reflexes,  but  the  cord  re- 
flexes are  not  so  much  depressed  as  by  chloral  or  bromides,  and 
the  tone  of  muscle  is  not  lost,  i.  e.,  there  is  no  essential  muscular 
relaxation.  Hence  morphine  is  not  good  in  strychnine  poisoning. 
Occasionally  in  fatal  poisoning  in  man  the  patient  has  manifested 
convulsions  of  the  strychnine  type.  It  is  possible  that  the  con- 
vulsant  action  is  produced  by  some  substance  derived  from  mor- 
phine in  the  body,  but  undoubtedly  asphyxia  plays  a  part  in  its 
production.  The  author  has  seen  typical  asphyxial  convulsions 
in  a  case  of  locomotor  ataxia  a  few  minutes  after  a  hypodermic  of 
y2  grain  (0.03  gm.). 

Medulla. — By  good-sized  therapeutic  doses  the  vagus,  vaso- 


OPIUM 


359 


constrictor,  and  pupil-contracting  centers  are  stimulated,  while 
the  respiratory,  the  cough,  the  temperature-regulating,  and  the 
secretory  centers  lose  their  sensitiveness. 

Peripheral  Nerves. — There  is  no  effect,  though  skin  sensitive- 
ness is  diminished  because  of  diminished  perception  of  stimuli. 

The  Eye. — After  good-sized  therapeutic  doses,  or  sometimes 
after  the  habitual  doses  of  a  morphine  devotee,  the  pupils  become 
contracted.  In  marked  poisoning  the  contraction  is  extreme  and 
makes  the  so-called  ''pin-point'1  pupils  which  are  characteristic 
of  opium  poisoning.  After  a  lethal  dose  the  pupil,  owing  to 
asphyxia,  very  widely  dilates  a  short  time  before  death,  so  that 
after  death  from  morphine  poisoning  the  pupils  are  found  to  be 
dilated.  In  animals  like  the  cat,  in  which  there  is  stimulation  of 
the  cerebrum,  morphine  dilates  the  pupil  from  the  beginning. 

Morphine  solution  dropped  in  the  eye,  or  injected  into  an 
enucleated  eyeball  (as  of  an  ox),  has  no  effect  upon  the  pupil,  so 
its  action  is  not  local  or  peripheral.  It  also  does  not  affect  the  eye 
through  the  third  nerve  ganglia  or  the  cervical  ganglia,  therefore 
its  action  must  be  purely  central.  That  it  stimulates  the  pupil- 
contracting  center  rather  than  depresses  the  pupil-dilating  center 
is  evident,  because  paralysis  of  the  latter  will  not  result  in  pin- 
point pupils,  or  produce  the  wide  dilatation  of  the  late  stage  of 
poisoning.  This  late  dilatation  is  probably  entirely  the  result  of 
asphyxia. 

The  Secretions. — From  depression  of  the  secretory  center 
almost  all  the  secretions  are  diminished,  but  this  is  a  minor  effect 
in  therapeutics.  The  sweat  is  increased,  but  not  markedly  so, 
unless  the  drug  is  given  with  a  copious  hot  drink.  In  health  the 
urine  is  not  essentially  changed;  but  in  nephritis  it  is  believed  by 
some  writers  to  be  decreased.  A  satisfactory  explanation  of  this 
is  not  forthcoming. 

Metabolism. — The  quiet  and  the  depressed  respiration  result 
in  lessened  tissue- waste  and  decreased  oxidation.  The  glycogen 
of  the  liver  may  disappear,  and  increased  lactic  acid  and  sugar 
appear  in  the  blood,  the  hyperglycemia  sometimes  resulting  in 
glycosuria. 

Temperature. — In  poisoning  the  fall  of  temperature  may  be 
as  much  as  2  degrees;  and  since  80  per  cent,  of  the  fall  is  due  to 
diminished  production  of  heat,  and  only  a  slight  amount  to  in- 
creased heat  dissipation,  the  drop  in  temperature  must  result 
from  the  bodily  quiet,  rather  than  from  the  dilatation  of  the 
cutaneous  vessels  and  sweating.  Morphine  is  not  employed  in 
therapeutics  as  an  antipyretic.  The  author  has  seen  fever  of 
102. 6°  F.  with  a  skin  rash  and  sickness  of  three  or  four  days 
follow  a  single  dose  of  morphine,  the  patient  reporting  that  this 


360  PHARMACOLOGY  AND   THERAPEUTICS 

was  his  second  experience  of  the  kind.  An  irregular  temperature 
has  been  reported  in  chronic  opium  takers. 

Excretion. — After  a  hypodermatic  injection,  the  drug  has  been 
found  in  the  mouth  in  two  and  a  half  minutes,  and  in  the  stomach 
in  three  minutes,  and  it  continues  to  be  found  in  the  stomach  all 
through  the  period  of  morphine  action  (Marme).  In  dogs,  about 
30  per  cent,  of  morphine  given  hypodermatically  can  be  recovered 
from  the  stomach,  a  fact  which  suggests  the  value  of  lavage  in 
poisoning.  About  30  or  40  per  cent,  more  may  be  recovered  in  the 
feces  (Faube,  Faust).  It  is  evident,  therefore,  that  a  certain 
amount  of  reabsorption  and  reexcretion  must  go  on  in  the  alimen- 
tary tract,  with  the  final  result  of  either  destruction  of  the  mor- 
phine or  its  discharge  with  the  feces.  Traces  of  morphine  also 
appear  in  the  milk,  sweat,  and  urine,  and  the  remainder  is  oxidized 
to  the  comparatively  inactive  oxydimorphine,  some  of  which  is 
excreted  in  the  urine.  Cloetta  was  unable  to  obtain  tests  of  mor- 
phine in  the  blood  after  twenty  minutes,  and  determined  that  it 
had  totally  disappeared  from  the  body  in  two  days. 

Rarely  some  morphine-glycuronic  acid  appears  in  the  urine 
and  may  react  with  Fehling's  solution.  Rarely  also  there  is  a 
true  glycosuria.  The  odorous  substances  of  opium  are  excreted 
mostly  in  the  urine. 

Though  it  is  found  in  the  fetal  blood,  it  does  not  seem  to 
affect  the  fetus,  probably  because  the  latter  does  not  maintain  its 
vitality  by  its  respiratory  apparatus.  The  new-born  babe  of  a 
habitue  may,  however,  require  its  habitual  dose  if  the  amount 
excreted  in  the  mother's  milk  is  insufficient,  or  if  the  child  is 
taken  from  the  breast.  If  a  large  dose  of  morphine  is  given  to 
a  non-habituated  mother  just  before  delivery,  it  may  disastrously 
affect  the  infant's  breathing. 

The  Bladder. — In  poisoning  there  may  be  failure  of  the  reflexes, 
and  spasm  of  the  sphincter  with  retention  of  urine. 

Kidneys. — Ordinarily  there  is  no  effect,  but  in  uremia  the  drug 
seems  to  increase  the  inefficiency  of  the  kidneys  (Tyson). 

After-effects. — Not  uncommon  after  a  medicinal  dose  are: 
nausea,  vomiting  and  constipation,  with  perhaps  headache,  dizzi- 
ness, and  general  lassitude.  For  a  short  time  after  a  hypoder- 
mic dose  there  may  be  a  very  slow  "vagus"  pulse. 

Untoward  Effects. — Excitement  instead  of  quiet,  an  effect 
seen  mostly  in  women,  and  common  among  eastern  women;  it 
is  the  regular  effect  in  cats.  Occasionally  there  is  diarrhea.  The 
author  has  observed  the  following  striking  untoward  effects,  viz. : 
(1)  Suspension  of  breathing  and  asphyxial  convulsions  in  a  case 
of  locomotor  ataxia.  (2)  Partial  heart-block  from  a  hypodermatic 
of  \  grain  (0.008  gm.).     (3)  Death  from  a  change  of  partial  heart- 


OPIUM  361 

block  to  complete.  On  several  occasions  even  small  doses  had 
caused  an  increase  in  the  block,  with  Cheyne-Stokes  respiration. 
The  fatal  dose,  ^  grain  (0.01  gm.),  was  given  by  a  newcomer  for 
terrific  pain.  (4)  A  mottled  rash  with  fever  of  102. 6°  F.,  and  pains 
in  the  joints.  (5)  Edema  of  the  lungs  in  a  case  of  myocarditis  and 
in  two  cases  of  pneumonia. 

Susceptibility. — Very  young  and  very  old  people  are  especially 
susceptible  to  morphine,  and  in  such  the  drug  must  be  used  with 
special  caution.  The  dose  should  be  below  that  called  for  by  the 
ordinary  rules  for  dosage.  The  too  ready  use  of  paregoric  for 
infants  cannot  be  too  strongly  condemned,  for  many  deaths  have 
occurred  from  its  employment,  and  in  numerous  instances  an 
opium  habit  has  been  formed. 

Tolerance  is  fairly  easily  set  up,  and  not  only  is  there  an  in- 
creased power  of  the  body-cells  to  oxidize  the  morphine,  but  also 
an  increased  resistance  of  the  cells,  so  that  they  are  affected  less 
strongly  by  the  same  amounts  of  morphine.  Faust  found  in  dogs 
that  the  ability  of  the  tissues  to  destroy  morphine  was  increased, 
so  that  as  tolerance  was  established  none  of  the  morphine  was 
excreted.  Riibsamen,  experimenting  with  rats,  and  Cloetta  with 
dogs  in  which  tolerance  had  been  established,  isolated  large 
quantities  of  unchanged  morphine  from  the  tissues.  Wholey 
reports  cases  taking  25  grains  (1.7  gm.)  and  60  grains  (4  gm.)  as 
the  daily  dosage.  We  have  encountered  a  case  that  was  reported 
to  be  receiving  96  grains  (6.4  gm.)  a  day. 

Toxicology. — Acute  poisoning  is  not  uncommon,  among  both 
children  and  adults.  Death  has  been  reported  from  about  3 
grains  of  morphine  sulphate.  A  single  large  dose  has  occasionally 
resulted  in  prompt  vomiting  and  the  expulsion  of  the  drug,  but 
this  is  unusual.  Practically,  the  poisoning  shows  three  stages  or 
degrees. 

Poisoning  in  the  first  degree  is  not  infrequently  seen  from  the 
physician's  administration  of  the  drug  to  relieve  pain.  There  are: 
Rather  slow  respiration,  slow  heart  but  good  blood-pressure,  and 
contracted,  though  not  pin-point,  pupils.  The  patient  is  sluggish 
and  inattentive,  may  or  may  not  be  sleeping,  and,  on  being 
spoken  to  or  asked  to  do  something,  may  rouse  up  for  a  time  and 
look  better  and  brighter;  but  he  soon  relapses  into  the  previous 
state  of  lethargy  and  inattention, or  sleep.  There  may  be  nausea, 
perhaps  retching  or  vomiting.  The  treatment  is  strong  coffee  by 
mouth  or  rectum,  or  hypodermatics  of  caffeine,  and  plenty  of  air. 
Atropine  and  strychnine  may  also  be  of  value.  Lavage  of  the 
stomach  is  sometimes  useful  to  lessen  nausea  and  remove  some  of 
the  drug. 

The  second  degree  of  poisoning  results  in  stupor,  a  stage  which 


362  PHARMACOLOGY  AND  THERAPEUTICS 

supervenes  in  from  fifteen  to  thirty  minutes.  The  face  is  cyanotic, 
flushed,  the  skin  warm,  the  respirations  regular,  and  only  4  to  10 
per  minute,  or  Cheyne-Stokes  in  character,  the  heart  slow,  though 
blood-pressure  remains  good,  the  pupils  pin-point,  and  the  patient 
in  a  state  of  unconsciousness  from  which  he  can  be  aroused  only 
with  great  difficulty.  When  aroused,  he  brightens  up,  has  in- 
telligence, can  talk  distinctly,  and  can  be  made  to  walk  about 
(difference  from  alcoholism) ;  but  if  allowed,  he  relapses  at  once 
into  sleep,  which  soon  again  becomes  a  deep  stupor.  There  may 
be  retention  of  urine. 

Treatment. — (1)  Potassium  permanganate,  1  to  2  grains  (0.06- 
0.12  gm.)  in  solution  at  intervals  by  mouth  to  oxidize  any  mor- 
phine that  may  be  in  the  stomach,  that  excreted  as  well  as  that 
which  has  not  been  absorbed.  (2)  Lavage  of  the  stomach  at 
intervals  with  water  or  1 :  2000  potassium  permanganate  solution. 
(3)  Colon  irrigation  to  remove  the  morphine  as  it  is  excreted,  and 
so  prevent  its  reabsorption.  (4)  The  hourly  administration  of 
maximal  doses  of  caffeine,  atropine,  or  black  coffee  until  the  de- 
pression of  respiration  is  overcome.  (5)  Ceaseless  activity — above 
all  things  keep  patient  awake  and  active,  for  in  this  stage  if  he 
relapses  into  sleep  the  patient  rapidly  and  seriously  loses  ground. 
As  the  heart  usually  continues  strong  and  there  is  no  muscular 
weakness,  vigorous  measures  may  be  employed  to  keep  him  ac- 
tive, e.  g.,  he  may  be  walked  about,  and  if  necessary  lashed  with 
a  wet  towel  or  whip.    (6)  Catheterization,  if  required. 

The  third  degree  of  poisoning  is  manifested  by  coma  and  col- 
lapse. The  patient  cannot  be  aroused,  the  skin  is  cyanotic,  cold, 
and  clammy,  the  pulse  is  weak,  the  respirations  are  very  infre- 
quent and  shallow — either  regular,  at  the  rate  of  three  or  four  a 
minute,  or  Cheyne-Stokes  in  type.  Rarely,  there  are  strychnine- 
like convulsions  or  the  convulsions  of  asphyxia.  Death  takes 
place  from  paralysis  of  the  respiratory  center.  Shortly  before 
death  the  pupil  may  widely  dilate.  The  treatment  is  that  for 
severe  collapse,  with  absolute  repose,  artificial  respiration,  oxy- 
gen, carbon  dioxide,  and  the  administration  of  caffeine.  The 
prognosis  after  the  patient  passes  into  this  coma  stage  is  exceed- 
ingly unfavorable. 

Morphine  Habit. — Chronic  Poisoning  or  Morphinism. — Opium, 
and  its  alkaloid  morphine,  are  vicious  habit-drugs,  the  habit  being 
common  among  physicians,  nurses,  and  druggists.  The  drug  may 
be  taken  by  hypodermatic  injection,  by  mouth,  or  by  the  inhala- 
tion of  opium  fumes  (opium  smoking).  The  last  method  is  said 
to  be  the  least  pernicious.  When  the  devotee  does  not  get  his 
usual  dose,  he  is  nervous,  restless,  irritable,  and  unable  to  con- 
centrate his  mind  upon  his  work;  when  he  gets  his  drug  he  ex- 


OPIUM  363 

periences  a  return  of  his  energy,  feels  comfortable,  and  is  in  better 
spirits.  He  soon  then  passes  into  a  dreamy,  imaginative  state  of 
mental  and  bodily  satisfaction,  i.  e.,  wholly  indifferent  to  outside 
influences,  and  forgets  his  responsibilities  and  his  troubles;  then 
comes  sleep,  usually  of  a  stuporous  kind,  and  on  awaking  there 
may  be  nausea,  headache,  languor,  and  nervousness. 

The  prolonged  use  frequently  results  in  digestive,  nervous, 
and  mental  troubles,  viz.,  loss  of  appetite,  nausea,  and  obstinate 
constipation;  irritability  of  temper,  loss  of  will-power  and  self- 
control,  mental  depression,  and  if  the  habit  is  a  bad  one,  a  ten- 
dency to  moral  depravity  (develop  low,  vulgar  tastes,  are  frightful 
liars,  etc.) ;  irregular  heart  tremors,  anemia  and  wasting,  some- 
times an  irregular  temperature,  polyuria,  and  perhaps  albumin- 
uria or  glycosuria,  and  often  sexual  impotence  and  amenor- 
rhea. At  the  Sloane  Maternity  Hospital  the  writer  delivered 
a  devotee  of  fourteen  years'  standing  whose  husband  had  been 
a  habitue  for  over  twenty  years.  The  child  was  not  well- 
nourished,  but  thrived  on  the  breast.  During  her  stay  in  the 
hospital  the  mother  received  her  daily  dosage. 

Treatment. — 1.  Isolation  from  friends  and  hirelings. 

2.  Gradual  withdrawal  of  the  drug  in  from  two  or  three 
days  to  a  week.  Accompanying  the  withdrawal  there  may  be 
diarrhea,  cramps  in  abdomen,  back,  and  legs,  intense  restlessness, 
and  mental  and  physical  suffering. 

3.  The  substitution  for  a  time  of  other  drugs,  of  which  great 
favorites  are  atropine,  hyoscine,  and  codeine.  Keeping  the  pa- 
tient in  a  state  of  partial  narcosis  for  several  days  tends  to  pre- 
vent the  discomforts  which  cause  the  craving  for  morphine. 

4.  Nourishing  food,  to  the  extent  of  overfeeding. 

5.  Massage,  baths,  and  general  measures  to  improve  the  hy- 
gienic conditions  of  living. 

In  morphinism  there  is  no  hereditary  neuropathic  tendency  as 
there  is  in  alcoholism,  and  the  cause  of  the  continuance  of  the 
morphine  habit  is  the  distress  of  the  withdrawal  symptoms.  The 
morphinist  will  often  desire  to  give  up  the  drug,  but  never  does 
so  of  his  own  free  will,  because  he  cannot  stand  the  physical  suf- 
fering. Yet  morphine  patients  have  a  greater  desire  to  reform 
than  alcoholics  have,  and,  when  once  reformed,  are  quite  likely 
to  remain  so,  unless  the  pain  or  worry,  etc.,  which  was  the  original 
cause  of  the  habit,  recurs.  Often  they  go  back  to  the  drug  for 
relief  from  suffering,  rather  than  because  of  any  special  craving 
for  it.  Stomach  symptoms  must  be  especially  guarded  against, 
as  they  are  always  attributed  to  abstinence  from  the  drug. 

Without  some  systematic  method  of  treatment  it  is  one  of  the 
most  difficult  tasks  to  check  a  morphine  habit,  and  the  habitue 


364  PHARMACOLOGY  AND  THERAPEUTICS 

will  take  paregoric,  and  even  Sun  Cholera  Drops,  for  the  morphine 
they  contain. 

The  cutting-off  of  the  habitual  dose  because  of  some  intercur- 
rent illness,  such  as  pneumonia,  causes  needless  suffering  and 
danger.  Collapse  for  want  of  the  drug  has  been  reported  in  in- 
fants born  of  habitues. 

Dr.  Alexander  Lambert  has  recently  outlined  a  method  used 
at  Bellevue  Hospital.  It  consists  in  the  administration  of  a 
specific  remedy,  of  decreasing  doses  of  the  opiate,  and  of  powerful 
cathartics.    It  is  as  follows: 

1.  The  specific  consists  of  a  mixture  of  15  per  cent,  tincture 
of  belladonna,  2  parts,  with  1  part  each  of  the  fluidextracts  of 
xanthoxylum  and  hyoscyamus.  It  is  administered  every  hour, 
beginning  with  6  drops  and  increasing  2  drops  per  dose  every  six 
hours.  It  is  continued  until  belladonna  symptoms  are  noticed 
or  there  is  a  thick,  green  stool. 

2.  The  opiate — after  the  first  free  catharsis  give  two-thirds 
the  total  habitual  daily  dose  of  morphine  or  opium  in  3  divided 
doses  at  half-hour  intervals.  After  the  action  of  the  second  dose 
of  the  cathartic  (about  the  eighteenth  hour)  give  one-third  the 
habitual  daily  dose.  About  the  thirty-sixth  hour,  give  one-sixth 
the  habitual  daily  amount.  If  very  nervous,  give  5  grains  (0.3 
gm.)  of  codeine  phosphate  hypodermatically. 

3.  The  cathartic — at  the  outset  give  5  compound  cathartic 
pills  and  5  grains  (0.3  gm.)  of  blue  mass,  followed  in  six  hours  by 
a  saline.  At  the  tenth  hour  after  the  first  dose  of  opiate  repeat 
the  pills  and  blue  mass,  and  six  hours  later  the  saline.  Ten  hours 
later  repeat  again,  followed  by  the  saline  if  necessary.  When  a 
thick,  bilious,  green  stool  appears,  give  2  ounces  of  castor  oil  to 
clean  out  the  intestines.  If  the  patient  is  weak,  give  strychnine 
or  digitalis. 

The  morphine  habitue  is  prone  to  be  an  abominable  liar,  and 
five  minutes  after  taking  the  dose  will  state  emphatically  that 
he  has  not  taken  the  drug  for  weeks.  Tablet  triturates  found  in 
the  possession  of  a  suspect  may  be  tested  as  follows:  Dissolve  one 
in  0.5  c.c.  (8  minims)  of  water,  and  add  2  drops  of  the  tincture 
of  ferric  chloride:  a  blue  or  bluish-green  color  indicates  morphine. 
Sometimes  needle  punctures  in  the  arms  or  legs  will  confirm  the 
diagnosis,  or  a  state  of  dopiness  with  contracted  pupils,  or  a  test 
with  a  dose  of  morphine  to  see  if  it  gives  great  satisfaction.  A 
peculiar  blue  coloration  of  the  skin  in  the  region  of  the  needle 
punctures  has  been  described  as  "pigment  atrophy."  The  author 
has  seen  a  striking  case. 

Therapeutics. — Morphine  or  opium  is  used  extensively  to 
allay  severe  pain,  and  to  overcome  restlessness  and  nervousness 


OPIUM  365 

or  anxiety  associated  with  sickness;  in  other  words,  to  promote 
ease  of  mind  or  body.    Some  of  its  more  special  uses  are: 

1.  To  check  vomiting. 

2.  To  stop  intestinal  peristalsis,  as  after  rectal  or  abdominal 
operations,  and  in  peritonitis;  and  to  check  excessive  peristalsis, 
as  in  intractable  diarrhea,  as  that  of  tuberculosis.  Paregoric,  or 
the  pills  of  lead,  2  grains  (0.12  gm.),  and  opium,  1  grain  (0.06 
gm.),  or  of  camphor  and  opium,  are  preferred,  but  hypodermics 
of  morphine  are  also  effective.  In  the  presence  of  acute  abdominal 
pain  one  should  avoid  opiates  if  possible  until  the  diagnosis  is 
determined. 

3.  To  quiet  a  nervous  heart,  or  rest  a  diseased  heart,  by  pro- 
moting general  rest  and  quiet. 

4.  To  lessen  pain. 

5.  To  relieve  the  pain  and  gastric  upset  in  migrainal  vomiting 
attacks. 

6.  To  relieve  the  pain  and  anxiety  of  angina  pectoris. 

7.  To  check  cough.  It  should  be  avoided  in  chronic  cough 
because  of  habit  formation. 

8.  To  lessen  worry  and  restlessness  in  acute  conditions,  such  as 
hemoptysis,  or  in  incurable  diseases,  such  as  cancer. 

9.  To  compel  quiet  and  sleep,  as  in  delirium  or  mania,  or  in 
spite  of  powerful  factors  which  tend  to  keep  the  patient  awake, 
such  as  pain. 

10.  As  a  preliminary  to  general  anesthesia,  to  quiet  the  mind 
and  promote  the  anesthesia.  It  is  frequently  given  with  hyoscine 
(scopolamine) .  Its  tendency  to  produce  dilatation  of  the  stomach 
and  to  depress  the  respiration  is  a  drawback  to  its  use. 

11.  To  induce  sweating  at  the  onset  of  a  cold,  in  the  form  of 
Dover's  or  Tully's  powder.    It  is  not  a  good  diaphoretic. 

12.  In  diabetes — opium,  morphine,  and  codeine  have  a  special 
power  to  bring  about  a  reduction  in  the  sugar  excretion;  and 
von  Noorden  attributes  this  to  the  quiet  of  the  body  and  the 
sleep  induced  by  their  use.  From  the  author's  experience  this 
explanation  of  the  action  seems  inadequate. 

Contraindications  or  Cautions. — It  should  not  be  used  in — (a) 
Conditions  with  much  depression  of  the  respiration,  as  in  edema 
of  lungs,  Cheyne-Stokes  breathing,  and  some  cases  of  pneumonia ; 
(b)  acute  dilatation  (paralysis)  of  stomach  or  bowels.  It  should 
be  employed  cautiously  in — (a)  nephritis,  especially  if  there  is 
any  uremic  tendency;  and  (b)  infancy  and  old  age. 

Atropine  is  frequently  given  with  morphine  in  hypodermatic 
use.  It  tends  to  supplement  the  good  effect  on  pain  and  to  lessen 
the  nausea;  but  its  most  important  effects  are  to  counteract  the 
depression  of  respiration  and  perhaps  the  vagus  stimulation. 


366  PHARMACOLOGY  AND   THERAPEUTICS 

CODEINE 

This,  the  methyl  ester  of  morphine,  is  a  weaker  narcotic,  and 
its  power  to  allay  pain  and  induce  sleep  is  very  much  less  than 
that  of  morphine.  Yet  where  the  lesser  effect  is  sufficient,  it  has 
the  following  advantages  over  morphine:  (1)  It  is  not  especially 
a  habit-drug;  (2)  it  is  not  strongly  constipating,  and  (3)  it  is  less 
depressing  to  the  respiration.  Further,  codeine  differs  from 
morphine  in  that  it  is  excreted  largely  by  the  kidneys. 

In  Heinz'  experiments  with  rabbits  a  dose  of  i}4  grains  (0.1 
gm.)  reduced  the  breathing  from  92  to  60  in  thirty-three  minutes, 
but  the  individual  inspirations  were  deeper,  so  that  at  the  eightieth 
minute  the  air  inspired  had  increased  from  720  to  1000  c.c.  per 
minute.  With  morphine,  one-twentieth  this  amount  reduced  the 
rate  of  respiration  and  also  the  expired  air  to  nearly  one-half. 

In  allaying  cough  it  is  just  as  effective  as  morphine,  but  its 
dosage  must  be  fully  six  times  as  large.  A  matter  of  note  is  that 
with  a  very  slight  increase  beyond  the  hypnotic  dose,  a  stimulat- 
ing effect  upon  the  cord  may  appear,  with  restlessness  and  in- 
creased reflex  excitability  instead  of  quiet  and  sleep.  Its  chief 
uses  are  to  allay  mild  pain,  especially  abdominal  pain,  to  promote 
sleep  (usually  with  other  hypnotics,  such  as  trional  or  veronal), 
to  quiet  cough,  and  in  diabetes.  In  a  chronic  disease  like  the 
last  mentioned,  and  in  tuberculous  cough,  codeine  is  just  as  useful 
and  is  preferred  to  morphine  because  of  the  ease  with  which  a 
morphine-habit  is  established.  The  usual  dose  of  codeine  for 
cough  is  l/i  grain  (0.015  gm-)>  and  for  pain,K  grain  (0.03  gm.), 
repeated  every  three  or  four  hours;  for  hypodermatic  use  the 
phosphate  is  preferred  because  of  its  solubility.  The  author  has 
seen  two  codeine  habitues — they  were  broken  of  the  habit  without 
any  trouble. 

DI-ACETYL  MORPHINE 

Di-acetyl  morphine,  or  heroine,  of  which  the  chloride,  soluble 
in  alcohol  and  water,  is  in  use,  is  somewhat  like  codeine,  its  powers 
to  diminish  pain  and  to  promote  sleep  being  less  than  those  of 
morphine,  while  its  tendency  to  produce  reflex  excitability  is 
greater.  It  is  excreted  partly  by  the  kidneys  and  partly  by  the 
intestines. 

In  Heinz'  rabbit  experiments,  -^  grain  (0.001  gm.)  caused  a 
reduction  of  the  respirations  from  120  to  18  in  forty  minutes  and 
reduced  the  volume  of  air  inspired  from  880  c.c.  per  minute  to 
240  c.c.  Hence  the  individual  inspirations  are  increased  in  depth, 
but  the  respiration  is  so  slowed  that  the  intake  of  air  is  consider- 
ably reduced.  It  is  about  five  times  as  depressing  to  the  respi- 
ration as  morphine,  and  Heinz  says  that  it  is  about  thirty  times 


DI-ACETYL  MORPHINE  367 

as  depressing  as  codeine;  while  Gottlieb  and  Magnus  state  that 
even  very  small  doses  may  show  a  dangerous  effect  upon  the 
center.  Worth  Hale  reports  it  as  depressing  to  the  circulation. 
In  over  100  cases  of  pulmonary  tuberculosis  the  author  made 
a  clinical  comparison  of  its  action  with  that  of  codeine,  giving 
each  drug  many  times  to  the  same  patient.  One-twelfth  grain 
(0.005  gm.)  of  heroine  chloride  was  compared  with  Y^  grain  (0.0015 
gm.)  of  pure  codeine,  or  y§  grain  (o.oi  gm.)  of  heroine  chloride 
with  y2  grain  (0.003  §m-)  °f  codeine.  The  codeine  proved  supe- 
rior in  its  power  to  allay  cough,  to  overcome  pain,  and  to  promote 
sleep.  In  several  cases  the  heroine  produced  nausea  and  consti- 
pation, and  in  one  woman  who  was  regularly  excited  by  morphine, 
heroine  produced  the  same  excitement,  while  codeine  did  not. 
Heroine  would  seem,  therefore,  to  possess  some  of  the  undesirable 
properties  of  morphine.  A  number  of  cases  of  heroine  habit  have 
been  reported,  and  some  of  them  have  proved  difficult  to  cure. 

1  have  one  old  patient  who  for  several  years  obtained  his  heroine 
in  certain  proprietary  cough  remedies;  he  was  easily  switched  to 
codeine  and  then  broken  of  the  habit.    Brooks  and  Mixell  report 

2  cases,  one  taking  6  ounces  (150  c.c.)  of  "gly co-heroin,"  a  pro- 
prietary remedy,  and  the  other  10  to  15  grains  (0.7-1  gm.)  of 
heroine  per  day.  Both  were  cured  through  the  substitution  of 
codeine.  Wholey  reports  a  case  using  hypodermatically  one 
hundred  ^-grain  tablets  a  day.  The  symptoms  after  withdrawal 
are  pains  in  shins  and  legs,  coarse  tremor  of  hands  and  fingers, 
nervousness,  headache,  insomnia,  and  stomach  discomforts.  In 
experiments  with  dogs  it  has  been  shown  that  tolerance,  [simi- 
lar to  that  from  morphine,  is  readily  established.  Many  cases 
among  young  men  of  the  use  of  heroine  by  snuffing  have  recently 
been  reported. 

The  chief  employment  of  heroine  is  to  check  cough. 

Dionine,  ethyl-morphine  chloride  is  soluble  in  water  and  al- 
cohol. In  dose  of  ^  to  1  grain  (  0.03-0.06  gm.)  it  is  not  so  seda- 
tive as  its  composition  would  seem  to  indicate,  but  it  is  employed 
more  or  less  for  cough  and  mild  pain.  It  is  analgesic  in  the  eye, 
and  has  been  extensively  employed  by  the  ophthalmologists  in 
treatment  of  deep-seated  ocular  pain.  Lloyd-Owen  finds  that  a  2 
to  5  per  cent,  solution  dropped  in  the  eye  has  scarcely  any  effect 
on  the  cornea  and  conjunctiva,  but  is  decidedly  analgesic  in  the 
presence  of  the  deep-seated  pains  of  iritis,  glaucoma,  etc.  It  does 
not  contract  the  pupil.  Several  oculists  have  reported  to  me  a 
primary  irritation  with  chemosis  lasting  an  hour  or  two.  It  is 
probable  that  its  action  is  not  local,  and  that  it  is  absorbed 
through  the  eye  to  act  on  centers. 


368  PHARMACOLOGY  AND   THERAPEUTICS 

CANNABIS  INDICA 

Indian  cannabis  is  "The  dried  flowering  tops  of  the  pistillate 
plants  of  Cannabis  saliva  (Fam.  Moracece),  grown  in  the  East 
Indies,  and  gathered  while  the  fruits  are  yet  undeveloped  and 
are  carrying  the  whole  of  their  natural  resin." 

The  plant  is  grown  extensively  in  various  countries  for  hemp 
fiber  and  seed,  the  seed  formation  being  accompanied  by  dimin- 
ished resin  production;  but  in  the  East  Indies  all  staminate  plants 
and  flowers  are  removed  so  as  to  prevent  setting  of  seed,  and  this 
results  in  a  greater  product  of  resin.  Under  the  names  of  bhang, 
char  as,  ganja,  hashish,  etc.,  various  preparations  of  the  drug 
are  used  in  the  East  as  habit-drugs. 

Constituents. — Ten  to  20  per  cent,  of  resin,  volatile  oil,  a 
bitter  principle,  and  traces  of  the  alkaloid  cannabinine  and  other 
alkaloids.  The  activity  resides  in  the  resin,  the  active  principle 
of  which  has  not  been  isolated.  Cannabinol  is  a  mixture,  chiefly 
oil  and  resin.  The  drug  as  marketed  is  very  variable  in  strength 
and  tends  to  deteriorate. 

Preparations  and  Doses. — Cannabis  Indica,  1  grain  (0.065 
gm.);  extract,  %  grain  (0.01  gm.);  fluidextract,  1  minim 
(0.065  c.c);  tincture  (10  per  cent.),  10  minims  (0.65  c.c). 

Action. — In  eastern  peoples,  among  whom  the  "hasheesh" 
habit  is  common,  it  produces  depression  of  the  highest  centers, 
setting  free  the  imagination,  and  resulting  in  an  agreeable, dreamy 
"dolce  far  niente"  state  resembling  that  from  morphine.  The 
sensation  of  pain  and  touch  are  lessened,  the  extremities  feel 
numb,  a  state  of  indifference  to  outside  influence  comes  on,  and 
sleep  may  follow. 

In  America  there  is  generally  no  intoxication  from  therapeutic 
doses,  but  a  mild  general  depression  of  the  intellectual  and  sen- 
sory centers  of  the  cerebrum  and  quieting  of  nervous  excitability. 
Dixon  recommends  the  inhalation  of  the  vapor  as  most  soothing. 
Like  morphine,  it  may  promote  sleep  in  the  presence  of  pain. 
From  poisonous  doses,  however,  there  is  delirious  intoxication, 
and  the  patient  may  lose  self-control,  laugh,  and  talk  at  random. 
His  sense  of  time  and  distance  may  be  lost,  and  he  may  fear  im- 
pending death.  Subsequently  there  is  general  cerebral  depression, 
resulting  in  sleep  or  stupor,  with  diminished  perception  of  pain 
and  muscular  relaxation.  The  heart  becomes  slow  and  weak,  and 
the  pupil  is  dilated.  Very  large  doses  have  been  recovered  from. 
An  interesting  description  of  the  effects  of  a  large  dose  upon 
himself  is  given  by  H.  C.  Wood,  Sr.,  in  his  "Therapeutics,  its 
Principles  and  Practice." 

Therapeutics. — Owing  to  its  great  variability,  its  tendency 
to  deteriorate,  and  great  differences  in  individual  susceptibility 


THE    ANTIHYSTERICS    (ANTISPASMODICS)  369 

to  its  action,  Cannabis  indica  is  very  little  employed.  A  good 
preparation  of  it  may  allay  nervous  excitability,  as  after  sexual 
or  alcoholic  excesses,  may  lessen  the  pain  of  neuralgia  or  migraine, 
and  may  promote  sleep  (in  the  presence  of  pain) .  As  obtainable, 
it  often  fails  to  have  any  therapeutic  effect. 


Humulus  (hops)  is  the  strobile  of  Humulus  lupulus  (Fam. 
Moracece) ,  bearing  the  glandular  powder  which  is  known  as"lu- 
pulin."  Lupulin  contains  resin,  volatile  oil,  bitter  lupamaric  acid, 
and  valeric  acid.  The  preparations  are  made  of  lupulin,  and  are: 
Fluidextract  of  lupulin,  dose,  3  minims  (0.2  c.c);  oleoresin  of 
lupulin,  dose,  3  grains  (0.2  gm.). 

The  drug  is  used  as  a  bitter,  and  as  a  mild  sedative  and  anti- 
spasmodic in  the  treatment  of  nervousness,  restlessness,  and 
hysteria.  A  hop  pillow  or  a  poultice  made  of  steamed  hops  is 
a  convenient  method  of  applying  heat  to  the  face,  back,  or 
shoulder,  as  in  toothache  and  neuralgia.  Its  specific  sedative 
virtues  exist  only  in  the  minds  of  the  laity.  The  hops  used  in 
the  manufacture  of  beer  contribute  to  its  hypnotic  powers. 

Lactucarium,  the  concrete  milk  juice  of  Lactuca  virosa  (Fam. 
Composite?) ,  is  said  to  be  narcotic,  like  opium,  but  its  action  is 
a  very  feeble  one.  The  syrup  (5  per  cent.)  made  from  the  tinc- 
ture (50  per  cent.)  is  employed  for  cough  and  as  a  sedative  for 
children;  dose,  2  drams  (8  c.c).  Lactucarium  lozenges  are  to  be 
had  for  cough.  One  of  the  most  famous  of  the  proprietary  lac- 
tucarium lozenges  was  found  to  contain  opium. 

THE  ANTIHYSTERICS    (ANTISPASMODICS) 
These  are  all  aromatic  carminative  drugs,  but  they  have  a 
tendency  beyond  that  of  other  carminatives  to  lessen  states  of 
nervous  instability  and  hysteria.    The  one  most  in  use  is  valerian; 
but  asafetida,  sumbul,  musk,  and  camphor  are  also  employed. 

Valerian  contains  0.5  to  2  per  cent,  of  a  volatile  oil  which  is 
composed  of  esters  of  valeric  acid,  chiefly  the  borneol  ester.  It 
has  the  usual  effect  of  a  volatile  oil  drug,  stimulating  the  motor 
functions  of  stomach  and  intestines  and  overcoming  flatulence 
and  colic;  and  reflexly,  and  perhaps  slightly  directly,  stimulating 
the  heart  and  the  vasoconstrictor  and  respiratory  centers.  It 
seems  to  exert  in  a  pronounced  manner  a  stimulant  effect  upon 
the  highest  cerebral  centers,  those  which  exert  psychic  control, 
so  that  states  of  nervousness  are  overcome.  Important  factors 
in  producing  the  cerebral  effects  seem  to  be  the  odor,  the  taste, 

and  the  volatile  oil  effect  on  the  stomach.     Free  valeric  acid 

24 


37°  PHARMACOLOGY  AND  THERAPEUTICS 

(valerianic  acid)  and  the  non- volatile  valerates  (valerianates), 
such  as  those  of  ammonium,  iron,  zinc,  and  quinine,  are  scarcely 
carminative  and  have  little  of  the  effect  of  the  liquid  preparations. 

Its  preparations  are  the  fluidextract,  dose,  }4  dram  (2  c.c), 
the  20  per  cent,  tincture  (made  with  alcohol  and  water),  and  the 
20  per  cent,  ammoniated  tincture  (made  with  aromatic  spirit  of 
ammonia),  dose,  1  dram  (4  c.c).  The  borneol  valerate  has  the 
properties  of  a  volatile  oil,  and  is  sometimes  given  in  5-  or  10- 
minim  capsules. 

Musk,  of  which  the  5  per  cent,  tincture  is  official,  dose,  1  dram 
(4  c.c),  is  the  dried  secretion  from  the  preputial  follicles  of  the 
musk-ox.  It  is  a  sex  stimulant.  It  is  very  expensive  (about 
$30  an  ounce),  therefore  its  use  in  medicine  is  limited  to  refrac- 
tory cases  of  hiccup  and  of  manifestations  of  hysteria. 

DRUGS   WHICH    CHIEFLY   AFFECT    THE    PERIPHERAL 
NERVOUS  SYSTEM 

I.  Those  which  depress  the  peripheral  nervous  system — the 
belladonna  group,  cocaine,  etc. 

II.  Those  which  stimulate  the  peripheral  nervous  system — pilo- 
carpus (jaborandi),  physostigma,  etc.  We  have  already  spoken 
of  adrenaline,  which  stimulates  sympathetic  nerve-endings. 

BELLADONNA   GROUP 

The  belladonna  group  includes  belladonna  (deadly  nightshade), 
stramonium  (jimson-weed  or  thornapple),  scopola,  and  hyoscya- 
mus  (henbane),  all  of  which  belong  to  the  potato  family,  the 
Solanacece.  and  have  similar  constituents  and  related  pharma- 
cologic actions. 

Occurrence. — Belladonna  (Atropa  belladonna)  is  a  purple- 
flowered  herb  of  central  and  southern  Europe  and  western  Asia. 
It  is  cultivated  for  the  market  in  England  and  Germany.  Scopola 
(Scopola  carniolica)  also  grows  in  Europe.  Stramonium  {Datura 
stramonium)  is  a  tall,  coarse,  narcotic  smelling  herb,  which  fruits 
with  a  spiny,  four-valved  capsule  the  size  of  a  walnut,  filled  with 
small  black  seeds.  It  grows  in  Asia,  Europe,  and  the  United 
States  east  of  the  Mississippi,  and  may  be  found  in  abundance 
in  the  vacant  lots  of  our  eastern  cities.  Poisoning  from  the 
swallowing  of  the  seeds  by  children  has  frequently  been  reported. 
Hyoscyamus  {Hyoscyamus  niger)  is  an  herb  native  to  Europe  and 
more  or  less  cultivated. 

Constituents. — The  active  principles  are  alkaloids,  the  chief 
of  which  are  atropine,  hyoscyamine,  and  hyoscine.  Atropine  is 
a  compound  of  equal  amounts  of  the  isomers,  dextro-  and  levo- 


BELLADONNA    GROUP 


371 


hyoscyamine,  into  which  it  separates  when  dissolved  in  water. 
Hyoscyamine  is  levo-hyoscy amine,  and  is  readily  changed  to 
dextro-hyoscyamine.  In  the  growing  belladonna  the  hyoscya- 
mine is  said  to  form  in  the  young  leaves,  to  be  later  changed  to 
atropine. 

According  to  the  predominance  of  one  or  other  of  these  alka- 
loids, and  to  the  amounts  present,  the  drugs  of  this  group  fall 
into  a  regular  pharmacologic  series,  as  follows: 

1.  Belladonna  (root  and  leaves) 
— the  leaves  contain  0.35  per 
cent.,  and  the  root,  0.5  per  cent., 
of  alkaloid,  which  is  nearly 
all  atropine.  It  has,  therefore, 
a  typical  atropine  action. 

2.  Scopola    (root)    contains    0.5 


Fig.  42.— Datura  stramonium,  Linne 
— flowering  branch   (Maisch). 


Fig.  43. — Capsule  of  stramonium 
(thornapple  or  jimson  weed).  The  seeds 
have  frequently  been  the  cause  of  poison- 
ing (Bastin). 


per  cent,  of  alkaloid,  about  equally  hyoscyamine  and 
atropine.  It  acts  like  belladonna,  but  with  somewhat 
less  strength. 
3.  Stramonium  (leaves)  contains  0.35  per  cent,  of  alkaloid, 
mostly  hyoscyamine,  but  with  small  amounts  of  atropine 
and  hyoscine.  It  is  less  stimulating  to  the  cerebrum  and  may 
be  narcotic. 

4.  Hyoscyamus  (leaves)  contains  0.08  per  cent,  of  alkaloid, 
mostly  hyoscyamine,  with  a  fair  amount  of  hyoscine,  and  only 
traces  of  atropine.  It  is  rather  narcotic,  but  is  weaker  than  the 
other  drugs  of  the  group. 

Preparations  and  Doses. — The  dose  of  belladonna,  scopola, 


37 2  PHARMACOLOGY   AND   THERAPEUTICS 

or  stramonium  is  i  grain  (0.06  gm.) ;  that  of  hyoscyamus,  4  grains 
(0.25  gm.).  The  doses  of  the  preparations  can  readily  be  esti- 
mated from  their  known  strengths.  The  official  preparations 
are: 

The  fluidextracts  and  extracts  of  belladonna   (fluidextract  of 
root,  extract  of  leaves),  of  scopola,  of  stramonium,  and  of 
hyoscyamus. 
The  10  per  cent,  tinctures  of  belladonna  leaves,  of  stramo- 
nium, and  of  hyoscyamus. 
In  addition : 

Of  belladonna,  the  liniment  is  made  by  adding  5  per  cent,  of 
camphor  to  the  fluidextract;  and  preparations  of  the  extract 
are:    the  ointment,  10  per  cent.;    the  plaster,  30  per  cent.; 
the  compound  laxative  pills,  y&  grain  (0.008  gm.)  in  each, 
and  the  pills  of  podophyllum,  belladonna,  and  capsicum,  y& 
grain  (0.008  gm.)  in  each. 
Of  stramonium,  the  ointment  contains  10  per  cent,  of  extract. 
Of   the   alkaloids,    the  dose  is  yi-Q-  grain    (0.0004  gm-)>  the 
maximum  beginning  dose  being  -V  grain   (0.0012  gm.).     The 
official  salts  are:    atropine  sulphate,  hyoscyamine  bromide,  hyos- 
cyamine sulphate,  hyoscine  bromide,  and  scopolamine  bromide,  all 
readily  soluble  in  water  and  alcohol.     Atropine  can  withstand 
the   heat   of  boiling   water   without   decomposition.     Hyoscine 
and  scopolamine  are  chemically  identical,  and  in  spite  of  claims 
to  the  contrary,  are  considered  by  pharmacologists  to  be  physi- 
ologically identical. 

Pharmacologic  Action  of  Atropine. — The  primary  actions  of 
the  group  are  those  of  atropine.  They  are — (a)  To  stimulate 
nerve-centers,  and  (b)  to  depress  nerve-endings. 

(a)  The  nerve-centers  which   atropine  primarily  stimulates 
are   the    cerebral  and  the   vital   medullary   centers.     Only   in 
highly  poisonous  doses  does  it  depress  these. 

(b)  The  nerve-endings  which  atropine  primarily  depresses  are: 

1.  The  sensory  nerve-endings — not  a  marked  effect,  but  tend- 
ing to  lessen  sensation  and  pain.  Short  and  Salisbury  (19 10) 
could  not  detect  any  cutaneous  anesthesia. 

2.  The  motor  nerve-endings  in  the  smooth  muscle  of  the  viscera 
(not  in  striated  muscle  and  arterial  muscle) — a  strong  effect, 
tending  to  allay  abnormal  contraction  of  the  muscles  of  the 
viscera  (bronchi,  stomach,  intestines,  bile-ducts,  etc.). 

3.  The  secretory  nerve-endings — a  very  strong  effect,  tending 
to  check  the  mucous,  digestive,  and  skin  secretions. 

4.  The  ends  of  the  third  nerve  in  the  eye — a  strong  effect. 

5.  The  vagus  nerve-endings — so  that  the  heart  is  freed  from 


BELLADONNA   GROUP  373 

the  usual  inhibitory  vagus  control — an  effect  that  is  striking 
but  short-lived. 

Atropine  depresses  primarily  these  nerve-endings,  whether 
it  is  applied  locally  or  given  internally,  while  it  has  no  effect 
at  all  upon  most  protoplasmic  structures.  It  is,  therefore,  a 
highly  selective  drug.  In  speaking  thus  of  nerve-endings  from 
a  practical  point  of  view,  it  should  be  noted  that  atropine  acts 
on  muscle  after  nerve  degeneration,  though  not  on  the  contractile 
substance  of  the  muscle;  hence  it  probably  affects  some  material 
which  acts  as  the  receptor  of  the  nerve  impulse.  It  is  some  part 
of  the  neuromuscular  junction,  though  we  speak  of  it  crudely 
as  the  nerve-ending. 

Absorption  and  Local  Action. — There  is  slight  absorption  from 
plasters,  and  fair  absorption  from  oily  and  alcoholic  preparations, 
as  ointments  and  liniments;  so  the  drug  may  have  an  effect 
through  the  skin  on  sensory  and  secretory  nerve-endings.  In 
tests  with  66  belladonna  and  scopola  plasters  Bastedo  and  Martin 
(1901)  found  that  these  had  distinctly  more  power  to  stop  pain 
than  had  the  simple  plaster  without  belladonna.  That  there  is 
some  absorption  from  plasters  is  shown  further  by  the  occasional 
occurrence  of  poisoning  from  them.  (See  Fig.  47.)  Absorp- 
tion is  ready  through  mucous  membranes,  the  drug  rapidly  dis- 
appearing from  stomach  and  duodenum. 

Alimentary  Tract. — The  chief  effects  of  the  drug  are  to  lessen 
secretion  and  overcome  colic  (spasmodic  contraction  with  pain). 
The  taste  is  bitter. 

(a)  Secretion. — After  atropine,  stimulation  of  the  chorda 
tympani  results  in  no  secretion  of  saliva.  This  is  not  due  to  the 
paralysis  of  the  center  or  ganglia,  for  stimulation  of  the  nerve 
peripheral  to  the  ganglia  still  produces  no  secretion.  Stimula- 
tion of  the  sympathetic,  however,  continues  to  cause  secretion 
and  vasodilatation,  hence  there  is  no  paralysis  of  the  secreting 
cells  themselves  or  of  the  vasodilating  fibers.  Therefore  the 
paralyzed  portion  is  the  connection  between  the  nerve  and  the 
secreting  cell,  i.  e.,  the  nerve-ending.  There  is  some  evidence 
that  in  large  amounts  atropine  slightly  depresses  the  secretory 
cells  themselves. 

In  the  mouth  the  saliva  and  mucous  secretions  are  lessened, 
and  the  throat  and  mouth  become  dry,  an  effect  which  is  often 
noticed  from  quite  small  doses.  If  marked,  the  patient  cannot 
swallow,  though  he  may  be  very  thirsty.  The  stomach  secre- 
tion is  less  affected,  but  is  probably  moderately  diminished. 
Riegel  states  that  this  is  especially  true  of  the  acid  portion  of  the 
gastric  juice. 

The  intestinal  secretions  tend  to  be  lessened. 


374  PHARMACOLOGY  AND   THERAPEUTICS 

The  secretion  of  the  pancreas,  though  under  the  influence  of  the 
vagus,  is  dependent  on  the  presence  in  the  blood  of  the  chemic 
substance  secretin,  rather  than  on  nerve  impulses,  so  atropine 
has  little  if  any  direct  effect  upon  the  amount  of  its  digestive 
elements.  But  through  depression  of  the  vagus  endings  it  may 
lessen  the  watery  portion  of  the  secretion. 

The  bile  production  has  been  shown  also  to  be  due  partly 
to  a  substance  in  the  blood,  probably  secretin,  and  its  production 
is  little,  if  any,  affected. 

It  is  of  interest,  however,  that  by  cutting  off  certain  nerve 
impulses  which  induce  the  change  of  glycogen  to  sugar,  atropine 
promotes  the  storing  of  glycogen  by  the  liver.  It  has  on  this 
account  been  recommended  by  Rudisch  (1909)  in  diabetes. 
Forchheimer  (191 1)  says  of  it:  "In  a  large  number  of  cases 
glycosuria,  and  with  it  acetone  bodies,  have  diminished  or  dis- 
appeared." But  in  the  very  careful  studies  of  two  diabetics 
by  Mosenthal  (191 2)  atropine  sulphate  in  amounts  which  gave 
beginning  poisonous  symptoms,  i.  e.,  up  to  y^y  grain  (0.0045 
gm.)  three  times  a  day,  showed  absolutely  no  effect  on  the  car- 
bohydrate tolerance. 

(b)  Motor  Activity. — Atropine  lessens  but  does  not  abolish 
the  vagus  power  over  the  intestine  (the  vagus  is  the  motor  nerve 
of  the  small  intestine),  so  that  the  effects  of  drugs  which  act  as 
cathartics  by  stimulation  of  the  vagus,  e.  g.,  physostigmine, 
may  be  checked;  while  the  peristalsis  from  cathartics  which  act 
by  direct  irritation  of  the  intestinal  wall,  and  not  through  the 
vagus  nerves,  is  apparently  not  affected.  This  is  because 
atropine  does  not  affect  the  automatic  motor  ganglia  of  Auer- 
bach's  plexus.  It  tends,  however,  to  check  the  so-called  "tone- 
waves"  without  checking  peristalsis;  and  when  from  over- 
irritation  or  from  vagus  overactivity  there  is  spasmodic  con- 
traction with  colicky  pains,  or  spastic  constipation,  atropine 
tends  to  overcome  this.  To  understand  this  action  we  must 
understand  the  difference  between  normal  peristalsis  and  in- 
testinal colic,  which  is  a  term  applied  to  any  localized  spasmodic 
painful  contraction  of  the  intestine. 

In  peristalsis  a  wave  of  contraction  precedes  the  stimulating 
body  in  the  intestine  by  about  an  inch,  while  the  bowel  relaxes 
below  the  stimulating  body  for  a  foot  or  two.  That  is  to  say, 
peristalsis  is  a  coordinated,  purposeful  action  involving  both 
stimulation  and  inhibition.  It  is  designed  to  propel  the  intestinal 
contents  forward  and  bring  them  into  contact  with  the  intestinal 
juices.  But  if,  instead  of  this  coordinated  wave  of  contraction 
and  relaxation,  there  is  a  spasmodic  contraction  of  the  intestine 
about  some  offending  body,  even  about  an  accumulation  of  gas, 


BELLADONNA    GROUP 


375 


or  preceding  an  obstruction  that  cannot  be  moved  onward,  there 
is  intestinal  colic  or  cramp;  at  the  same  time  the  contents  are 
not  propelled  along,  so  there  is  constipation.  In  such  a  case 
atropine,  by  allaying  the  spasm,  may  permit  normal  peristalsis 
to  be  restored,  and,  as  a  consequence,  cause  a  disappearance  of 
both  the  cramp  and  the  constipation.  Irritant  cathartics  some- 
times cause  this  kind  of  colic,  i.  e.,  they  tend  to  gripe,  and  to  these 
atropine  or  one  of  the  extracts  is  frequently  added  as  a  corrective. 
The  constipation  and  colic  of  peritoneal  irritation,  anemia,  lead 
poisoning,  or  fecal  impaction  may  be  overcome  by  atropine, 


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Fig.  45. — Chart  showing  the  effects  of  atropine  on  the  heart-rate  of  a  patient 
with  vagus  slowing  from  digitalis.  The  numbers  at  the  side  represent  pulse  beats, 
those  at  the  top,  minutes   (James  Mackenzie,  in  "Heart,"  vol.  ii.  No.  4,  191 1). 


but  if  the  obstruction  is  immovable,  i.  e.,  of  surgical  nature, 
atropine  obviously  has  no  value. 

Heart. — The  vagus  center  is  stimulated,  but  any  effect  from 
this  is  soon  prevented  by  depression  of  the  vagus  nerve-endings, 
so  that  from  large  doses  there  regularly  results  a  faster  and  some- 
what stronger  heart-beat.  In  the  mammal  no  direct  action  upon 
the  muscle  is  distinguished,  though  in  the  frog  a  dose  of  atropine 
will  temporarily  revive  an  exhausted  heart.  The  largest  dose 
ordinarily  employed  for  humans  hypodermatically  is  -^  grain 
(0.0012  gm.);  its  effect  on  the  vagus  is  seen  in  about  twenty 
minutes,  and  lasts  less  than  one  hour. 


37^  PHARMACOLOGY  AND  THERAPEUTICS 

Arteries. — The  vasoconstrictor  center  is  slightly  stimulated, 
and  this,  with  the  increased  rate  of  the  heart,  causes  a  rise  in 
arterial  pressure.  This  is  easily  demonstrated  in  a  dog.  The 
contraction  of  the  arteries  is  most  marked  in  the  splanchnic  area. 
In  man,  however,  the  rise  in  blood-pressure  from  even  maximal 
therapeutic  doses  is  usually  inappreciable.  In  poisoning  the 
vasoconstrictor  center  tends  to  be  depressed. 

The  Cutaneous  Arterioles. — From  poisonous  amounts  the 
arteries  of  the  skin,  especially  those  of  the  head  and  neck,  are 
dilated;  and  a  flushed  face  or  an  erythematous  rash  like  that  of 
scarlet  fever  is  characteristic  of  atropine  poisoning.  The  flushed 
skin  is  from  a  central  action,  as  there  is  no  flushing  if  the  sympa- 
thetic in  the  neck  is  divided. 

Respiration. — A  dose  of  atropine  is  followed  by  deeper  and 
more  rapid  breathing  and  a  considerable  increase  in  the  amount 
of  air  inspired.  This  is  largely  due  to  stimulation  of  the  respira- 
tory center;  but  since  the  increase  is  not  so  great  when  the 
afferent  vagus  libers  from  the  lungs  are  cut,  there  must  also  be 
some  peripheral  action.  This  is  probably  depression  of  the 
sensory  ends  of  the  vagi  in  the  bronchi,  for  stimuli  through  these 
usually  slow  respiration. 

The  drug  is  much  used  in  narcotic  poisoning,  especially  that 
from  morphine.  Vollmer  (1892)  reported  that  a  dog  inspiring 
4500  c.c.  of  air  per  minute  was  given  0.06  gm.  morphine  sulphate 
at  8.45.  At  3.40  the  air  inspiration  was  4000  c.c.  Then  atropine 
0.003  §m-  was  giyen>  and  in  fourteen  minutes  the  inspiration 
was  6000  c.c;  in  twenty-one  minutes,  10,000  c.c.  But  excessive 
doses  exhaust  the  center,  and  must  be  guarded  against  in  the 
use  of  the  drug  as  an  antidote.  Exhaustion  of  the  center  is  the 
cause  of  death. 

The  secretions  of  nose,  throat,  and  bronchi  are  diminished, 
so  that  the  membranes  are  dry  and  the  mucus  thick  and  tenacious. 
Excessive  contraction  of  the  bronchial  muscles,  as  in  spasmodic 
asthma,  is  overcome  by  depression  of  the  bronchomotor  vagal 
nerve-endings. 

Cerebrum. — The  effect  from  therapeutic  doses  is  very  little, 
but  after  poisonous  amounts  there  is  psychic  stimulation,  and  the 
patient  becomes  talkative  and  wakeful,  without  any  pronounced 
intellectual  stimulation  like  that  from  caffeine.  The  poisoning 
may  go  on  to  a  delirium,  usually  of  cheerful,  loquacious  type, 
and  may  even  result  in  maniacal  excitement.  Cerebral  depres- 
sion does  not  generally  ensue  until  the  centers  have  become  ex- 
hausted, and  then  there  may  follow  mental  confusion  and  nar- 
cosis leading  to  sleep,  stupor,  and  coma.  In  therapeutic  amounts 
the  drug  is  not  a  narcotic. 


BELLADONNA    GROUP  377 

The  motor  areas  are  also  stimulated  by  poisonous  doses,  as 
shown  by  the  increased  response  to  electric  stimulation  of  the 
exposed  brain  and  by  the  restless  activity.  The  general  ex- 
hilaration observed  after  overdoses  is  known  as  the  "belladonna 
jag,"  but  though  it  superficially  resembles  that  from  alcohol, 
it  is  true  stimulation,  as  shown  by  the  increased  excitability  of 
the  motor  areas  and  the  large  doses  necessary  to  depress  the 
intellectual  powers. 

The  medulla,  after  therapeutic  doses,  shows  strong  stimula- 
tion of  the  respiratory  center,  with  weak  stimulation  of  vagus 
and  vasoconstrictor.  Death  takes  place  from  exhaustion  and 
paralysis  of  the  respiratory  center. 

The  spinal  cord  is  stimulated  by  large  doses,  the  increase  in 
reflex  excitability  being  manifested  by  twitching  of  the  muscles. 
In  the  late  stages  of  poisoning  twitching  may  also  result  from 
asphyxia. 

The  peripheral  nerves  have  already  been  spoken  of. 

Comparing  atropine  with  caffeine  and  strychnine  as  central 
stimulants,  we  might  say  that,  in  therapeutic  doses,  all  three 
stimulate  the  medullary  centers,  and  of  these  chiefly  the  re- 
spiratory; but  that  caffeine,  in  addition,  stimulates  the  intel- 
lectual functions,  and  strychnine  the  spinal  or  reflex  functions. 

Eye. — Atropine  has  four  important  effects  on  the  eye:  It 
dilates  the  pupil,  paralyzes  accommodation,  increases  intra-ocular 
tension,  and  lessens  pain. 

(a)  The  Dilatation  of  the  Pupil. — The  iris  consists  of  two  sets 
of  muscles — the  circular,  supplied  by  the  third  nerve,  and  the 
radial,  supplied  by  the  sympathetic  fibers  from  the  superior 
cervical  ganglion.  These  two  sets  of  muscles  are  in  constant 
action,  and  by  opposing  each  other  constitute  an  exceedingly 
sensitive  balanced  mechanism  for  the  regulation  of  the  size  of 
the  pupil.  Dilatation  of  the  pupil  may  result  from  circular 
depression  or  radial  stimulation;  contraction  of  the  pupil  from 
circular  stimulation  or  radial  depression,  and  these  stimulations 
or  depressions  may  be  of  center,  ganglia,  nerve-endings,  or 
muscle- fibers. 

When  a  1  per  cent,  aqueous  solution  of  atropine  sulphate  is 
dropped  in  a  man's  eye,  the  pupil  dilates  in  about  fifteen  or  twenty 
minutes,  but  takes  two  hours  more  to  reach  the  maximum  dila- 
tation. There  is  no  effect  on  the  other  eye.  If  atropine  is  in- 
jected into  an  excised  mammal  eye,  the  pupil  dilates,  and  if  an 
animal  is  atropinized,  stimulation  of  the  third  nerve,  either 
central  or  peripheral  to  the  ciliary  ganglia,  is  without  effect  on 
the  pupil.  The  action  is,  therefore,  a  purely  peripheral  one. 
But  it  is  not  a  direct  effect  upon  the  muscle,  for  in  the  atropinized 


378  PHARMACOLOGY  AND   THERAPEUTICS 

animal  direct  stimulation  of  the  circular  muscle  results  in  con- 
traction; therefore  the  site  of  the  paralyzing  action  of  the  drug 
must  be  confined  to  the  third-nerve  endings  or  the  neuromuscular 
junction. 

The  dilatation  from  atropine  is,  therefore,  the  result  of  the 
unopposed  action  of  the  radial  muscles.  It  is,  however,  fre- 
quently strong  enough  to  break  weak  adhesions  between  cornea 
and  iris,  or  to  make  an  iris  which  is  strongly  attached  at  two 
points  bow  out  between  the  points  of  attachment.  The  pupil 
gradually  regains  its  power,  but  is  not  fully  restored  to  normal 
for  one  or  two  weeks. 

That  there  is  no  stimulation  of  the  radial  mechanism  is  evi- 


Fig.  46. — Increased  convexity  of  the  lens  during  accommodation.  The  solid 
white  outline  of  the  lens,  /,  shows  its  form  when  relaxed.  The  dotted  line  shows 
the  increased  curvature  of  the  anterior  surface  during  accommodation,  and  its 
advancement  forward  into  the  anterior  chamber,  a.  z  is  the  suspensory  ligament; 
m,  the  ciliary  muscle;  and  i,  the  iris  (Landolt). 


dent,  for,  after  atropine,  stimulation  of  the  cervical  sympa- 
thetic results  in  a  still  greater  dilatation;  and,  in  addition,  after 
removal  of  the  superior  cervical  ganglion  and  the  subsequent 
degeneration  of  the  sympathetic  nerve-fibers,  atropine  fails  to 
dilate  the  pupil. 

A  drug  which  causes  dilatation  of  the  pupil  is  called  a  mydri- 
atic. Belladonna  gets  its  name  from  this  mydriatic  action  (bella, 
beautiful;  donna,  lady),  which  makes  the  eye  seem  bright  and 
sparkling. 

(b)  Accommodation  depends  essentially  on  the  curvature 
of  the  crystalline  lens,  and  this  curvature  is  regulated  by  the 
ciliary  muscle.  When  the  ciliary  muscle  contracts,  the  capsule 
of  the  lens  relaxes,  and  the  elastic  lens  bulges  forward  and  be- 


BELLADONNA    GROUP  379 

comes  more  convex,  i.  e.,  accommodates  for  near  objects.  But 
when  this  muscle  is  paralyzed,  the  capsule  of  the  lens  is  drawn, 
the  lens  is  more  flattened,  and  it  is  impossible  to  focus  the  sight 
on  near  objects.  A  drug  that  paralyzes  accommodation  in  this 
manner  is  a  cycloplegic.  Atropine  is  strongly  cycloplegic.  This 
effect  on  accommodation  does  not  take  place  until  some  time 
after  the  pupil  has  begun  to  dilate,  and  it  wears  off  more  quickly 
than  the  effect  on  the  pupil;  but  until  the  power  of  accommoda- 
tion is  nearly  restored,  the  patient  cannot  read  or  see  near  objects 
clearly. 

In  fitting  glasses  paralysis  of  accommodation  is  necessary. 
A  1 :  200  solution  of  atropine  sulphate  usually  paralyzes  accommo- 
dation in  one  hour,  but  restoration  does  not  take  place  for  several 
days. 

(c)  Intra-ocular  Tension. — The  normal  eyeball  tension  depends 
chiefly  on  two  factors,  viz.,  (i)  The  amount  of  intra-ocular  secre- 
tion, and  (2)  the  freedom  with  which  fluids  may  escape  through 
the  efferent  lymph- channels,  i.  e.,  through  the  spaces  of  Fontana 
at  the  margin  of  the  pupil,  into  the  canal  of  Schlemm.  The 
tension  may  be  raised  either  by  extra  secretion  or  by  dilatation 
of  the  pupil  which  results  in  shutting  off  the  spaces  of  Fontana. 
It  is  by  dilatation  of  the  pupil  that  atropine  causes  the  increase 
of  tension.  In  glaucoma,  a  disease  in  which  the  tension  is  al- 
ready high,  atropine  may  produce  a  dangerous  condition;  and 
even  when  there  is  merely  a  glaucomatous  tendency,  it  may  pre- 
cipitate an  attack  of  glaucoma. 

(d)  Pain. — Atropine  gives  moderate  relief  from  the  pains  of 
iritis  and  other  intra-ocular  inflammations. 

Since  atropine  is  highly  selective,  the  same  ocular  effects 
may  be  seen  after  the  internal  administration  of  large  doses. 
An  antagonist  of  atropine  is  physostigmine,  which  stimulates  the 
ends  of  the  third  nerve.  It  is  not  powerful  enough  to  remove 
the  effects  of  atropine  at  once,  but  greatly  lessens  the  time 
which  the  eye  takes  to  return  to  normal. 

Muscles. — Probably  no  direct  action.  The  smooth  muscle 
of  the  viscera  is  weakened  by  the  depression  of  motor  nerve- 
endings  mentioned  above. 

Secretions. — Those  of  the  alimentary  tract  have  already  been 
spoken  of.  No  drug  has  greater  power  to  check  the  sweat  and 
mucous  secretions.  It  does  not  directly  affect  the  amount  of 
bile  or  urine. 

Sweat. — Stimulation  of  the  sciatic  nerve  of  a  normal  cat 
regularly  induces  sweating  of  the  foot.  In  an  atropinized  animal 
sweating  cannot  be  induced.  The  profuse  sweating  of  pilocarpine 
is  checked  by  atropine,  also  the  sweating  from  certain  other  drugs, 


380  PHARMACOLOGY   AND   THERAPEUTICS 

such  as  aspirin  and  phenacetin;  also  the  night-sweats  of  tuber- 
culosis. 

Milk. — After  all  the  nervous  connections  are  severed,  the 
breasts  still  have  the  power  to  secrete  milk,  though  the  secre- 
tion is  less  in  amount.  Hence  atropine,  which  merely  cuts  off 
the  nervous  influences,  tends  to  reduce  the  milk  secretion  very 
little,  and  cannot  cause  the  complete  stoppage  of  the  secretion. 
The  drug  acts  when  applied  to  the  breasts,  as  well  as  when  taken 
by  mouth. 

Temperature. — In  poisoning  it  is  characteristic  that  the 
temperature  may  rise  several  degrees.  The  author  saw  a  case 
with  a  temperature  of  1060  F.  According  to  Ott,  this  is  due  to 
the  absence  of  sweating,  for  no  rise  of  temperature  takes  place 
in  animals,  such  as  dogs,  which  do  not  sweat  and  are  therefore 
not  dependent  upon  sweating  as  a  means  of  lowering  tempera- 
ture.    Others  think  it  is  an  effect  upon  the  heat-regulating  center. 

Elimination. — A  considerable  portion  of  the  drug  is  oxidized, 
the  remainder  being  eliminated  rapidly  by  the  kidneys.  It  is 
said  to  disappear  from  the  body  inside  of  thirty-six  hours,  but 
the  prolonged  effect  on  the  eye  indicates  that  some  is  retained 
in  that  location. 

Urinary  Organs. — The  effect  on  the  amount  of  urine  from 
therapeutic  doses  is  uncertain  and  unimportant;  but  in  poisoning, 
both  suppression  and  retention  are  reported.  As  the  urine  is  a 
weak  solution  of  atropine,  it  will  exert  a  remote  local  action  in 
the  urinary  tract  to  lessen  pain  and  spasm.  In  poisoning,  the 
urine,  concentrated  by  boiling,  will  dilate  the  pupil  of  an  animal's 
eye ;  hence  this  may  be  employed  as  a  test  for  the  poison. 

Toxicology  of  Atropine. — In  practice,  the  dilated  pupils,  the 
dry  throat,  and  mild  cerebral  symptoms  are  the  regular  warnings 
of  overdosage.  In  full  poisoning  there  is  a  stage  of  central  stimu- 
lation followed  by  collapse.  In  this  stage  of  stimulation  the 
skin  is  warm  and  dry;  the  face  and  neck  are  flushed,  either 
uniformly  or  in  blotches,  to  resemble  the  skin  of  scarlet  fever; 
the  pupils  are  widely  dilated,  and  accommodation  paralyzed, 
so  that  vision  is  disordered;  the  throat  is  very  dry  and  red, 
and  there  is  a  feeling  of  constriction,  so  that  swallowing,  even  of 
water,  is  difficult,  though  the  patient  may  be  thirsty;  the  breath 
is  foul;  the  pulse  is  rapid,  with  arterial  pressure  above  normal; 
respiration  is  rapid  and  deep;  the  patient  is  wide-awake,  excit- 
able, restless,  and  loquacious  or  overcheerful,  and  may  pass  into 
a  chattering  delirium  with  confused  ideas,  or  even  into  a  condi- 
tion resembling  mania.  The  temperature  may  rise  several 
degrees.  The  concentrated  urine  dropped  in  a  cat's  eye,  two 
drops  every  five  minutes,  will  dilate   the  pupil.     Belladonna 


Fig.  47. — General  eruption  following  application  of  a  belladonna  plaster  (W.  S. 
Gottheil  in  Archives  of  Diagnosis). 


BELLADONNA    GROUP  381 

poisoning  has  been  mistaken  for  scarlet  fever  and  for  acute 
mania;  with  the  latter  diagnosis  patients  have  been  confined 
in  asylums  for  the  insane. 

Following  this  stage  of  stimulation  comes  collapse,  with  heart 
very  feeble,  blood-pressure  low,  respiration  slow  and  shallow, 
etc.  The  warm,  dry  skin  may  change  to  a  cold,  clammy  one, 
and  death  take  place  from  failure  of  respiration. 

A  single  dose  of  ^  grain  (0.0006  gm.)  of  atropine  sulphate 
will  in  some  patients  cause  dryness  of  the  throat  and  dilated 
pupil;  -V  grain  (0.0012  gm.)  has  produced  the  delirium,  y2  grain 
(0.03  gm.)  has  proved  fatal,  and  3  grains  (0.2  gm.)  have  been 
recovered  from. 

Atropine  may  remain  in  the  dead  body  for  a  long  time  un- 
changed. This  is  of  importance  from  a  medicolegal  point  of 
view,  for  the  atropine  may  be  mistaken  for  a  ptomain,  ptomatro- 
pine,  which  has  similar  chemic  and  pharmacologic  properties. 

Tolerance. — To  a  certain  degree  tolerance  may  be  set  up  in 
man  by  gradual  increase  in  the  dosage,  so  that  as  much  as  ^2 
grain  may  be  borne  without  ill  effects.  Children  can  take 
proportionally  large  doses;  in  fact,  a  child  of  eight  may  be  given 
the  same  dose  as  an  adult.  I  have  seen  a  man  of  forty-five  more 
affected  by  doses  of  10  minims  of  the  tincture  of  belladonna  than 
was  his  son  of  eight  by  the  same  amount.  Among  subhuman 
mammals  it  is  found  that  the  carnivora  are  especially  susceptible 
to  the  drug,  while  the  herbivora  are  markedly  resistant.  A  cat, 
for  instance,  is  readily  poisoned,  while  a  horse  or  a  rabbit  may 
feed  on  belladonna  leaves  with  comparative  impunity,  though 
their  flesh  becomes  poisonous  to  the  carnivora.  Successive  lit- 
ters of  healthy  rabbits  have  been  reared  entirely  on  belladonna 
and  stramonium  leaves,  and  Calmus  found  that  it  took  15  grains 
of  atropine  to  kill  a  small  rabbit. 

Treatment  of  Poisoning. — The  stomach  may  be  lavaged,  with 
or  without  a  solution  of  tannic  acid  or  tea  (Sollmann  says  that  tea 
is  an  inferior  precipitant  for  alkaloids).  For  the  delirium  and 
mania  an  ice-cap  may  be  applied  to  the  head,  whisky  or  bromides 
administered,  and,  if  necessary,  ether  inhaled  to  lessen  the  ex- 
citement. (Morphine,  chloral,  and  chloroform  should  be  avoided 
because  of  their  tendency  to  precipitate  respiratory  failure.)  In 
the  collapse  stage  the  regular  treatment  is  that  for  severe  collapse. 
Pilocarpine  and  physostigmine  antagonize  the  atropine  action 
on  certain  nerve-endings,  but  as  the  poisoning  is  dependent 
upon  the  cerebral  and  medullary  effects,  these  peripheral  an- 
tagonists are  not  antidotes  of  any  great  value. 

Therapeutics  and  Administration. — A.  To  Diminish  Secre- 
tion.— 


382  PHARMACOLOGY   AND   THERAPEUTICS 

i.  Of  mucus — as  in  excessive  secretion  from  nose,  throat,  and 
bronchi.  In  bronchitis,  in  the  free  running  stage  of  cold 
in  the  head,  the  rhinitis  tablets,  one  every  hour  for  6  doses, 
are  favorites.  Their  formula  is  ]4  grain  each  of  camphor 
and  quinine  sulphate  or  bisulphate,  and  %  minim  of  fluid- 
extract  of  belladonna.  They  are  often  employed  in  half 
this  strength. 

2.  Of  sweat — as  the  liniment  of  belladonna  in  sweating  of 

hands  and  feet,  and  atropine  internally  for  the  night- 
sweats  of  tuberculosis. 

3.  Of  milk — when  excessive,  or  when  it  is  desired  to  dry  up 

the  breasts — liniment  or  ointment  externally;  or  the  drug 
internally. 

4.  Of  saliva — as  in  profuse  salivation  from  any  cause — the 

drug  internally. 

5.  Of  gastric  juice — as  in  hyperacidity  and  hypersecretion,  Tg-5- 

grain  atropine  sulphate  or  -^j  grain  extract  of  belladonna 
fifteen  or  twenty  minutes  before  meals. 

B.  To  relax  over  contracted  smooth  muscle — as  in  spasmodic 
asthma  and  spasm  of  smooth  muscle  (colic).  The  latter  occurs 
in  the  esophagus,  cardia  (cardiospasm),  pylorus  (pylorospasm) , 
ileocecal  valve,  or  any  part  of  the  stomach  or  intestine,  in  the 
bile-passages  (biliary  colic) ,  in  the  pelvis  or  ureter  of  the  kidney 
(renal  colic) ,  in  the  neck  of  the  bladder,  and  in  spasmodic  dys- 
menorrhea (in  this  last  mentioned  the  drug  may  be  of  little  use 
because  of  the  congestive  condition).  Atropine  or  extract  of 
belladonna  may  be  added  to  irritant  cathartics  as  a  corrective 
to  prevent  griping. 

In  the  obstipation  which  occurs  in  lead-poisoning  and  in 
local  peritoneal  irritation  (as  in  appendicitis,  salpingitis,  or 
ovaritis,  or  renal  or  biliary  colic)  atropine  may  overcome  the 
reflex  spasm  with  resultant  catharsis.  In  intestinal  obstruction 
from  suspected  spasm,  or  in  fecal  impaction,  a  large  dose,  yg- 
grain  (0.005  gm-),  nas  been  recommended.  But  when  there  is  a 
real  surgical  obstruction,  such  a  procedure  serves  only  to  delay 
operation,  and  sometimes  with  fatal  result. 

C.  To  depress  the  sensory  nerve-endings — to  allay  itching  (the 
liniment) ;  to  lessen  pain,  as  in  ulcer  of  the  leg,  anal  fissure,  or 
projecting  hemorrhoids  (the  ointment) ;  and  the  drug  by  mouth 
for  irritable  bladder  or  urethra,  as  in  cystitis  and  urethritis,  and 
in  enuresis  nocturna. 

D.  In  the  eye — as  a  mydriatic,  cycloplegic,  and  analgesic,  for 
the  following  purposes : 

1.  To  facilitate  examination  of  the  internal  eye  posterior  to 
the  pupil. 


BELLADONNA    GROUP  383 

2.  To  paralyze  accommodation  in  fitting  glasses. 

3.  In  inflammatory  conditions  of  either  external  or  internal 

eye,  to  give  rest  to  iris  and  ciliary  muscle,  to  lessen  pain, 
and  to  prevent  the  spread  of  the  inflammation  to  the  iris; 
and  in  iritis,  to  prevent  the  formation  of  adhesions  to  the 
lens  or  cornea,  or  to  rupture  newly  formed  adhesions. 
It  is  employed  in  ^2  to  i  per  cent,  solution,  and  takes  a  long 
while  for  full  dilatation.     As  the  dilatation  of  the  pupil  and 
paralysis  of  accommodation  last  several  days,  atropine  is  espe- 
cially useful  in  the  inflammatory  conditions;   while  for  examina- 
tions and  fitting  glasses  more  rapidly  acting  drugs  are  preferred. 
After  the  continued  use,  for  a  few  days,  the  return  to  normal 
may  be  delayed   for  twelve  to  fourteen  days  (de  Schweinitz), 
but  the  restoration  may  be  greatly  hastened  by  the  use  of  phy- 
sostigmine.     De  Schweinitz  says  that  in  the  use  of  atropine  to 
correct  errors  of  refraction  one  drop  should  be  dropped  into  the 
eye  three  times  during  the  day  preceding  the  examination;    and 
in  hypermetropic  eyes,  especially  those  with  spasm  of  accommoda- 
tion, the  drug  should  be  used  for  several  days  before  the  examina- 
tion for  refractive  errors. 

E.  In  certain  spasmodic  nervous  conditions,  as  in  whooping- 
cough  (perhaps  enuresis  nocturna  under  this  head). 

F.  In  exophthalmic  goiter  (hyperthyroidism)  it  probably  acts 
by  decreasing  the  glandular  secretion.  (Sollmann  states  that 
atropine  is  antagonistic  to  thyroiodin.)  Bromides  should  be  given 
at  the  same  time,  as  the  cerebral  effects  of  belladonna  are  un- 
desirable in  this  disease. 

G.  As  preliminary  to  general  anesthesia — here  it  is  of  use  to 
check  excessive  secretion  in  mouth  and  respiratory  passages,  to 
stimulate  the  respiratory  center,  and  in  chloroform  anesthesia 
to  prevent  excessive  reflex  vagus  stimulation  at  the  onset. 

H.  To  stimulate  respiration,  as  in  general  anesthesia,  in  pneu- 
monia, or  in  collapse  from  narcotic  drugs;  to  prevent  respiratory 
depression,  as  when  given  with  morphine. 

I.  To  check  excessive  vagus  action,  as  in  the  excessive  inhibi- 
tion stage  of  chloroform  anesthesia,  and  in  vagus  bradycardia  or 
irregularity  of  the  heart  from  disease  or  from  a  drug  of  the  digi- 
talis group.  In  many  human  experiments  with  hypodermatic 
doses  the  author  was  unable  to  get  vagus  effects  with  less  than 
-jjV  grain  (1  gm.).  Thomas  Lewis  (191 1)  says  that  "atropine 
has  never  been  known  to  abolish  the  whole  hindrance  to  con- 
duction."    The  effects  last  not  more  than  an  hour. 

J.  In  anaphylaxis ,  as  in  serum  sickness.  In  experiments  on 
guinea-pigs  sensitized  with  horse-serum,  Auer  (1910)  reports  that 


384  PHARMACOLOGY  AND  THERAPEUTICS 

without  atropine  75  per  cent,  died,  and  with  atropine  only  28  per 
cent.  died. 

All  the  drugs  of  the  group,  viz.,  belladonna,  scopola,  stra- 
monium, and  hyoscyamus,  have  actions  of  the  atropine  type,  and 
can  be  used  interchangeably  for  the  ordinary  peripheral  effects. 

A  special  use  of  the  stramonium  leaves  is  in  spasmodic  asthma, 
in  which  condition  smoke  of  the  burning  leaves  is  inhaled.  The 
leaves  may  be  burned  in  a  saucer,  either  alone  or  with  other  drugs, 
or  impregnated  with  potassium  nitrate  (that  is,  saturated  with  a 
solution  of  potassium  nitrate  and  then  dried);  or  they  may  be 
added  to  tobacco,  lobelia,  or  cubebs,  and  made  into  cigars  or 
cigarettes  to  be  smoked  at  the  time  of  the  attack.  The  leaves  of 
belladonna  will  serve  as  well  as  those  of  stramonium. 

The  chief  use  of  hyoscyamus  is  as  a  sedative  in  irritable 
bladder,  cystitis,  and  gonorrhea,  and  as  a  corrective  addition  to 
irritant  cathartic  pills.  It  has  no  advantages  over  belladonna 
and  is  much  weaker. 

Hyoscyamine  (levo-hyoscy amine)  is  similar  in  action  to  atro- 
pine, which  is  a  mixture  of  levo-  and  dextro-hyoscyamine.  Cushny 
finds  that  though  it  acts  upon  the  central  nervous  system  with 
the  same  intensity  as  atropine,  it  is  nearly  twice  as  powerful  in 
its  effects  upon  nerve-endings,  especially  those  of  the  chorda 
tympani,  of  the  third  nerve  in  the  eye,  and  of  the  vagus.  It  is 
not  readily  obtained  pure,  and  is  little  employed  in  medicine. 
Dose  of  its  salts,  tfif  grain  (0.0004  gm-)- 

Hyoscine  or  scopolamine  acts  peripherally  like  atropine,  and 
therefore  will  allay  pain,  will  dilate  the  pupil,  and  will  check 
secretion.  But  its  action  in  the  eye  is  more  rapid  and  more 
powerful,  a  1  :  500  solution  dilating  the  pupil  in  ten  to  thirty 
minutes.,  and  quickly  thereafter  paralyzing  accommodation, 
while  the  effect  passes  fully  away  in  three  to  five  days.  Centrally 
it  differs  from  atropine  in  that  the  period  of  cerebral  stimulation 
is  short  and  is  followed  by  prolonged  mild  depression  of  the  psy- 
chic and  motor  centers — that  is,  the  drug  is  narcotic.  In  ex- 
citable states,  as  in  delirium  or  mania,  it  seems  to  have  great 
power  to  lessen  restlessness  or  excessive  motor  activity.  Its 
use  is  not  without  danger,  however,  for  it  shows  early  depression 
of  the  respiratory  and  vasoconstrictor  centers,  and  in  a  great 
number  of  instances  has  caused  collapse.  Eshner  and  O'Hara 
report  cases  of  collapse  after  ytu  grain  (0.0006  gm.)  of  the 
bromide.  The  writer  has  seen  fatal  collapse  from  Jg-  grain 
(0.0012  gm.)  in  an  alcoholic  man  with  pneumonia;  and  collapse 
with  recovery  from  y1-  grain  (0.0025  gm-)  m  an  alcoholic 
woman  verging  on  delirium  tremens.  In  both  of  these  the  hyos- 
cine had  been  preceded  by  *4  grain  (0.015  gm.)  of  morphine 


BELLADONNA   GROUP  385 

sulphate.     Collapse  is  reported  from  the  use  of  the  drug  in  the 
eye. 

Its  chief  uses  are: 

1.  As  narcotic  in  the  insomnia  and  excitement  of  acute  mania, 
in  delirium  tremens,  in  the  delirium  of  pneumonia  (especially  in 
alcoholics),  and  in  the  insomnia  of  alcoholism. 

2.  As  a  narcotic  and  peripheral  sedative  in  treating  the  mor- 
phine and  alcoholic  habits. 

3.  As  an  anaphrodisiac. 

4.  As  a  mydriatic  and  cycloplegic — one  drop  of  a  1  :  500 
solution  every  fifteen  minutes  for  four  to  six  drops. 

5.  As  a  general  anesthetic  or  as  a  preliminary  to  general  anes- 
thesia. 

Scopolamine-morphine  Anesthesia. — Under  the  name  sco- 
polamine, hyoscine  has  been  employed  quite  extensively  in  con- 
junction with  morphine,  and  it  must  be  considered  in  its  use — 
(a)  as  an  anesthetic,  and  (b)  as  a  preliminary  to  general  anesthe- 
sia. As  an  anesthetic,  about  -jjrs  grain  (0.0003  §m-)  °f  scopola- 
mine bromide  and  )/&  grain  (0.008  gm.)  of  morphine  sulphate 
are  injected  two  and  one-half  hours,  one  and  one-half  hours,  and 
one-half  hour  before  the  operation.  This  quite  frequently  re- 
sults in  the  abolition  of  pain.  Many  authors  have  spoken  well 
of  this  method  of  anesthesia  in  obstetrics  and  surgery;  but  in  69 
per  cent,  of  1988  cases  gathered  from  the  literature  by  Wood,  the 
anesthesia  proved  unsatisfactory,  and  in  a  number  of  instances 
had  to  be  supplemented  by  ether.  In  addition,  though  the  cases 
were  in  general  less  serious  than  the  average  ether  case,  there  were 
9  deaths  which  could  beyond  reasonable  doubt  be  attributed  to 
the  drug,  i.e.,  1  in  221.  Staff  en  reported  its  use  in  320  obstetric 
cases,  and  concluded  that  the  desired  results  were  not  obtained, 
that  it  was  dangerous  to  mother  and  child,  and  that  it  necessi- 
tated close  watching  of  the  patient,  because  of  the  possibility 
of  nausea,  vomiting,  excitement,  delirium,  or  collapse.  There 
are  many  reports,  both  favorable  and  unfavorable,  a  great  many 
considering  it  inefficient  and  dangerous  as  a  general  anesthetic. 

As  a  preliminary  to  general  anesthesia  with  ether,  a  single  dose 
of  the  mixture  of  hyoscine  and  morphine  is  quite  generally  recom- 
mended by  a  number  of  writers,  for  it  promotes  a  tranquil, 
drowsy  state  of  the  mind  which  favors  anesthesia,  it  lessens  the 
amount  of  ether  required,  and  it  diminishes  the  throat  and  bron- 
chial secretions. 

Homatropine  bromide  (U.  S.  P.)  is  the  bromide  of  an  arti- 
ficial alkaloid  allied  to  atropine  (it  is  made  by  the  condensation 
of  tropine  and  oxytoluic  or  mandelic  acid).  It  is  soluble  in  5.7 
parts  of  water,  and  is  used  solely  for  its  ocular  effects,  one  drop 


386  PHARMACOLOGY  AND  THERAPEUTICS 

of  the  i  per  cent,  solution  being  dropped  in  the  eye  every  fifteen 
minutes  for  4  to  6  drops.  Dilatation  of  the  pupil  comes  on 
quickly,  reaches  its  maximum  in  one  to  two  hours,  and  is  followed 
very  soon  by  paralysis  of  accommodation.  The  restoration  of  the 
accommodation  to  normal  occurs  in  twenty-four  hours,  and  full 
restoration  of  the  pupil  in  forty-eight  to  seventy-two  hours— 
i.  e.,  much  more  quickly  than  after  atropine. 

Homatropine  is,  therefore,  preferred  to  atropine  for  fitting 
glasses  and  in  ophthalmoscopic  examinations;  while  atropine  is 
preferred  where  continuous  mydriasis  is  desired,  as  in  inflamma- 
tory conditions  of  the  eyeball.  Physostigmine  will  hasten  the 
restoration  of  the  eye. 

Euphthalmine  has  the  same  relation  to  eucaine  that  hom- 
atropine bears  to  tropacocaine.  One  or  two  drops  of  a  5  per  cent, 
solution  of  the  chloride  will  rapidly  dilate  the  pupil  without 
paralyzing  the  accommodation.  It  is  of  no  use  in  fitting  glasses, 
though  it  may  be  employed  to  examine  the  posterior  eye. 

ANIDROTICS 

An  anidrotic  (anhydrotic)  is  a  remedy  which  tends  to  reduce 
sweating.  For  local  sweating,  as  of  the  hands  and  feet,  alcohol, 
eau  de  cologne,  spirit  of  camphor,  and  belladonna  liniment  are 
favorites.  For  odorous  perspiration  of  the  feet  alcohol  may  be 
used  as  a  wash,  and  a  mixture  of  boric  and  salicylic  acids  placed 
in  the  shoes  or  stockings. 

The  chief  use  of  a  general  anidrotic  is  in  the  night-sweats  of 
tuberculosis.  (See  discussion  under  Antipyretics  and  Dia- 
phoretics.) The  anidrotic  measure  may  be  a  hot  bath  on  going 
to  bed,  or  a  body  sponge  with  alcohol,  vinegar  (or  acetic  acid), 
or  a  solution  of  alum;  or  it  may  be  a  drug  taken  internally. 
Atropine  is  our  most  powerful  anidrotic.  It  has  the  advantage 
of  stimulating  respiration,  but  it  has  the  undesirable  effects  of 
drying  the  throat  and  increasing  the  cough,  and  may  even  dilate 
the  pupil.  In  very  extensive  tests  the  author  found  that  for 
internal  administration  the  best  general  anidrotic  is  agaricin. 
Strychnine  is  also  of  value.  Ergot,  which  has  been  highly  recom- 
mended, seemed  to  have  no  effect  at  all. 

Agaricin  is  an  unofficial  extract  obtained  from  the  fungus, 
Polyporus  albus,  which  grows  on  the  European  larch.  It  is 
really  an  impure  form  of  the  crystalline  principle,  agaric  acid. 
Its  dose  is  yV  grain  (0.006  gm.).  In  this  dose  it  strongly  de- 
presses the  ends  of  the  secretory  nerves  of  the  sweat-glands,  has 
no  undesirable  side-effects,  and  is  strongly  anidrotic;  but  its 
effects  are  not  lasting,  so  it  must  be  given  within  four  or  five 


COCA  387 

hours  of  the  expected  sweat.  If  the  sweat  comes  on  toward 
morning,  the  dose  may  have  to  be  repeated  once  in  the  night. 
In  larger  doses  it  sometimes  induces  nausea,  vomiting,  diarrhea, 
and  perhaps  dryness  of  the  throat,  but  it  does  not  dilate  the 
pupil.  Doses  large  enough  to  produce  nausea  do  not  give  the 
anidrotic  action. 

Camphoric  acid,  C8Hi4(COOH)2,  is  an  oxidation  product  of 
camphor.  It  is  soluble  in  alcohol  and  the  fixed  oils,  and  slightly 
in  water.  Its  dose  is  15  grains  (1  gm.),  given  in  cachet  or  powder. 
Its  taste  is  disagreeable,  and  its  systemic  action  is  mildly  that 
of  camphor;  but  practically  its  sole  use  in  medicine  depends  upon 
its  anidrotic  property.  Roth  (191 1)  found  it  to  be  without 
any  direct  effect  upon  the  sweat-glands,  and  was  disposed  to 
attribute  its  action  in  the  night-sweats  of  tuberculosis  to  stimu- 
lation of  the  respiratory  center. 

COCA 

Coca  is  the  dried  leaves  of  Erytkroxylon  coca,  or  of  Erythroxy- 
lon  truxillense  (Fam.  Erythroxylacece) ,  yielding,  when  assayed, 
not  less  than  0.5  per  cent,  of  its  ether-soluble  alkaloids.  The 
coca  shrub  is  extensively  cultivated  at  an  elevation  of  3500  to 
6000  feet  in  the  mountains  of  Peru,  Bolivia,  and  Ecuador,  and 
to  some  extent  also  in  Mexico  and  the  East  and  West  Indies. 
It  has  been  estimated  that  100,000,000  pounds  of  the  leaves  are 
used  annually  in  South  America. 

Constituents. — Cocaine  and  several  other  alkaloids,  all  com- 
pounds of  ecgonine.     Cocaine  is  the  methyl-benzoic  acid  com- 
pound; cinnamyl-cocaine  is  the  cinnamic  acid  compound,  and 
truxilline  is  the  truxillic  acid  compound. 
Preparations  and  Doses. — 
Coca,  0.5  per  cent,  alkaloid,  30  grains  (2  gm.). 
Fluidextract,  0.5  per  cent,  alkaloid,  30  minims  (2  c.c). 
Wine,  6.5  per  cent,  of  fluidextract,  with  red  wine,  etc.,  4 
drams  (15  c.c),  this  dose  containing  not  less  than  yj 
grain  cocaine. 
Cocaine     chloride    (hydrochloride)    is    the    alkaloidal    salt 
employed;    dose,  ]/2  grain  (0.03  gm.).     The  5  per  cent. 
oleate  of  cocaine  is  official. 
Cocaine  chloride,  C17H21NO4.HCI,  is  soluble  in  0.4  part  of 
water  and  2.6  parts  of  alcohol,  and  is  insoluble  in  the  oils.     (For 
oily  solution,  the  pure  alkaloid  must  be  employed.)    It  is  decom- 
posed at  a  temperature  of  about  980  C,  so  its  aqueous  solution 
cannot  be  sterilized  by  boiling.     Its  solutions  are  not  antiseptic, 
and  frequently  show  a  growth  of  mold.     This  mold  development 
may  be  retarded  by  the  addition  of  boric  acid.     The  following 


388 


PHARMACOLOGY   AND   THERAPEUTICS 


formulae  show  the  close  relation  between  atropine,  cocaine,  and 
tropacocaine. 


Tropine 
CH2 CH CH> 


CH2- 


CH2 


NCH3    CHOH 

I  I 
CH CH2 

Ecgonine 


Atropine 
CH2 CH CH 

/ 


CH2 


NCH3        CH.O.COCH^^1* 
\  CH.2U.ti 


-CH CH2 


Cocaine 


/ 


-CH CH.COOH     CH2 CH- 


-CH.COOCH3 


NCH3        CHOH 
\  I 

CH2 CH CH, 


NCH3        CH.O.CO.C6H5 

I           \  I 

CH2— CH CH2 


Tropacocaine 
CH2 CH CH, 

/  I 

NCH3       CH.O.CO.C6H6 

\  I 

CH2 CH CH2 


Pharmacology. — Coca  leaves  and  their  preparations  are  em- 
ployed only  to  a  very  limited  extent,  and  chiefly  in  the  form  of 
coca  wine;  but  cocaine  is  of  great  importance  pharmacologically, 
for  it  is  very  extensively  employed  as  a  local  anesthetic,  has 
marked  poisonous  properties,  and  is  one  of  the  vicious  "habit- 
drugs." 

Local. — Cocaine  is  a  general  protoplasmic  poison,  capable 
of  irritating  and  destroying  cells,  or  of  stopping  the  motions  of 
leukocytes,  amebae,  and  ciliated  cells.  Solutions  about  5  per 
cent,  in  strength  injected  hypodermatically  may  result  in  death 
of  tissue,  which  shows  either  as  a  necrotic  area  of  the  skin  or  as 
a  sterile  abscess;  the  application  to  the  eye  may,  for  the  same 
reason,  result  in  cloudiness  or  ulceration  of  the  cornea.  This 
effect  is  not  usually  seen,  but  it  occurs  often  enough  to  be  of 
importance. 

From  application  to  mucous  membranes  or  injection  beneath 
the  skin  there  promptly  follows  complete  abolition  of  pain, 
from  depression  of  the  ends  of  the  sensory  nerves  or  their 
adjacent  nerve-fibrils.  In  addition,  there  is  local  constriction 
of  the  arterioles  from  stimulation  of  both  muscle  and  vasocon- 
strictor nerve-endings.  The  constriction  of  the  vessels  is  not  so 
great  as  that  from  adrenaline.  The  anesthesia  and  constriction 
come  on  in  one  to  four  minutes  and  last  from  fifteen  minutes 
to  one  hour. 

The  drug  cannot  penetrate  the  unbroken  skin.  The  author 
kept  a  finger  for  fifteen  minutes  in  a  20  per  cent,  aqueous  solution 


COCA  389 

of  cocaine  chloride,  and  it  showed  neither  anesthesia  nor  blanch- 
ing, though  one  drop  of  the  liquid  on  the  tongue  was  quickly- 
followed  by  loss  of  sensation.  But  cocaine  is  readily  absorbed 
through  mucous  membranes  or  the  moist  parts  of  the  vulva. 
After  the  injection  or  application  there  may  be  a  momentary  ir- 
ritation, but  very  quickly  there  is  complete  loss  of  the  sense  of 
pain,  with  shrinkage  and  paling  of  the  part  from  comparative 
bloodlessness.  Any  mucous  membrane  to  which  the  drug  can  be 
directly  applied  becomes  shrunken  and  anesthetic  in  this  way, 
e.  g.,  membranes  of  the  nose,  throat,  mouth,  esophagus,  stomach, 
rectum,  vagina,  urethra,  bladder,  and  conjunctiva.  In  the  hypo- 
dermatic use  the  drug  is  injected  just  beneath  the  epidermis,  and 
its  action  is  prolonged  and  intensified  by  the  addition  of  adrena- 
line. This  further  constricts  the  vessels  and  prevents  the  too 
ready  removal  of  the  cocaine  by  the  circulation.  For  the  same 
reason  it  tends  to  make  the  skin  incision  bloodless.  In  a  finger 
or  toe  the  same  effect  may  result  from  the  application  of  a  tour- 
niquet or  band  to  impede  the  venous  return  flow. 

In  the  anesthesia,  though  the  sense  of  pain  is  promptly  lost, 
the  sense  of  touch  is  not  so  readily  abolished,  and  the  tempera- 
ture is  scarcely  affected,  if  at  all;  hence  the  touch  of  an  instru- 
ment or  the  heat  of  a  cautery  may  be  felt,  though  pain  is  absent. 
The  drug  at  first  tastes  bitter,  but  the  taste  for  bitter  soon  be- 
comes completely  abolished,  while  that  for  sweet  and  sour  merely 
becomes  dulled,  and  taste  for  salt  is  not  affected.  If  applied  in 
the  nose,  the  sense  of  smell  is  abolished. 

It  has  been  found  that  anesthesia  is  produced  if  the  drug  is 
applied  to  any  part  of  the  nerve,  from  the  nerve-ending  to  the 
posterior  root;   so  anesthesia  in  therapeutics  may  be  obtained — - 

(a)  by  the  application  of  the  solution  to  a  mucous  membrane; 

(b)  by  its  injection  beneath  the  mucous  membrane  or  skin;  (c) 
by  its  injection  into  the  nerve;  or  (d)  by  its  injection  into  the 
spinal  canal,  so  that  it  may  reach  the  posterior  roots.  This  last 
method  is  known  as  "spinal  analgesia"  or  "spinal  anesthesia." 
Cocaine  has  not  the  marked  selective  action  of  atropine,  but  from 
10  c.c.  of  1  to  3  per  cent,  solution  Ritter  (1909)  obtained  in  dogs 
a  general  anesthesia  lasting  from  fifteen  to  thirty  minutes.  The 
dogs  were  fully  awake,  but  quiet  and  indifferent  and  insensitive 
to  pain. 

The  drug  affects  sensory  nerves  very  readily,  but  not  so  readily 
the  motor  nerves.  If  both  sciatics  of  a  frog  be  exposed  high  up  in 
the  thigh,  and  a  little  cocaine  injected  into  the  substance  of  one 
of  them,  an  electric  stimulus  to  the  nerve  on  the  uncocainized 
side  (or  above  the  cocainized  area  on  the  other  side)  produces 
the  usual  reflex  results,  notably  contraction  of  the  splanchnic 


39°  PHARMACOLOGY   AND   THERAPEUTICS 

arteries.  But  no  such  results  follow  the  electric  stimulation  of 
the  cocainized  nerve  below  the  area  of  injection.  Evidently, 
then,  the  afferent  impulses  on  the  cocainized  side  are  blocked  and 
do  not  pass  the  cocaine. 

But  the  electric  stimulation  of  the  sciatic  above  the  cocain- 
ized area  produces  the  usual  muscular  contraction  in  the  leg  be- 
low, so  that  motor  impulses  are  not  blocked  by  the  cocaine.  There 
is,  perhaps,  a  slight  hindrance  to  the  passage  of  motor  impulses, 
as  mentioned  by  Crile. 

Spinal  Analgesia. — To  obtain  spinal  analgesia,  %  or  }4  grain 
(0.015-0.03  gm.)  of  cocaine  chloride  in  aqueous  solution  is  in- 
jected into  the  spinal  canal,  the  needle  being  inserted  between  the 
third  and  fourth  lumbar  vertebrae  into  the  region  of  the  cauda 
equina.  The  toes  and  perineum  become  anesthetic  in  about 
three  or  four  minutes,  and  the  anesthesia  rapidly  ascends  until 
it  reaches  about  to  the  umbilicus,  the  whole  of  the  body  below 
this  point  being  anesthetized.  There  is  little  or  no  muscular 
relaxation;  the  sense  of  touch  may  not  be  altogether  abolished, 
and  the  sensations  of  heat  and  cold  are  unchanged.  (See  also 
Shock  and  Collapse.) 

Jonnesco  has  recently  made  the  injections  higher  up  in  the 
spinal  cord,  using  a  mixture  of  stovaine  and  strychnine.  He 
reports  using  the  method  without  a  fatality  in  1005  patients, 
ranging  from  one  month  to  eighty-two  years.  Transient 
arrest  of  respiration  occurred  seven  times.  He  reports  1958 
cases  of  its  use  by  others  with  safety.  But  this  method  has  not 
met  with  favor  in  this  country,  and  after  many  trials  has  been 
abandoned  as  unsafe.  Experimentally,  it  has  been  shown  that 
cocaine  injected  into  the  spinal  canal  can  absolutely  block  the 
strychnine  convulsions  of  that  region,  but  the  strychnine  con- 
vulsions come  on  in  the  muscles  supplied  by  the  uncocainized 
parts  of  the  cord.  Gabbett  (1910)  reports  a  death  from  the 
injection  of  novocaine,  1%  grains  (0.6  gm.),  and  strychnine 
hydrochloride,  Th  grain  (0.001  gm.).  The  convulsions  affected 
the  arms,  but  not  the  legs. 

The  Eye. — If  a  drop  of  2  or  4  per  cent,  aqueous  solution  of 
cocaine  chloride  is  dropped  into  the  eye,  the  immediate  effect  is 
marked  irritation,  with  reflex  contraction  of  the  pupil.  But  this 
is  followed  quickly  by  anesthesia  of  cornea  and  conjunctiva,  with 
blanching,  retraction  of  the  eyelids,  and  absence  of  the  winking 
reflex  in  response  to  an  irritant.  A  few  minutes  later  the  pupil 
becomes  dilated,  and  remains  so  for  one  or  two  hours.  The  pu- 
pil, however,  still  reacts  to  light,  and  there  is  neither  paralysis  of 
accommodation  nor  decrease  in  intra-ocular  tension,  so  the  effect 
on  the  eye  is  different  from  that  produced  by  atropine.     This  is 


COCA  391 

further  shown  by  the  fact  that  in  a  fully  atropinized  eye  cocaine 
still  further  dilates  the  pupil,  and  that  in  a  cocainized  eye  the 
pupil  contracts  on  electric  stimulation  of  the  third  nerve,  either 
centrally  or  distally  to  the  ciliary  ganglia.  These  experiments 
show  that  it  does  not  act  on  the  third  nerve. 

The  action  of  the  cocaine  is  evidently  a  peripheral  one.  If 
it  is  injected  into  an  excised  eye,  it  causes  the  same  dilatation  of 
the  pupil.  Yet,  as  shown,  the  action  is  not  on  the  circular 
muscles  or  the  third-nerve  endings.  Therefore  the  dilatation 
must  be  due  to  stimulation  of  either  the  radial  muscle-fibers  or 
some  part  of  their  (sympathetic)  nerve-supply. 

If  the  superior  cervical  ganglion  (from  which  the  pupil-dilat- 
ing fibers  emanate)  is  removed  from  one  side  of  an  animal,  and 
after  the  wound  has  healed  and  the  nerves  have  had  time  to  de- 
generate, cocaine  is  dropped  in  each  eye,  there  is  a  dilatation  of 
the  pupil  on  the  intact  side,  but  not  on  the  other  side.  (In  some 
cases,  after  removal  of  the  ganglion  there  is  slight  dilatation,  and 
this  is  attributed  to  the  presence  of  sympathetic  fibers  which  do 
not  come  from  the  ganglia.) 

The  dilatation  from  cocaine  is,  therefore,  dependent  upon  the 
integrity  of  the  sympathetic  nervous  mechanism,  and  is  due  to  a 
stimulation  of  the  sympathetic  nerve-endings.  There  is  probably 
some  shrinkage  of  the  iris  from  contraction  of  its  vessels,  but  this 
is  of  no  moment.  Since  the  third  nerve  and  the  circular  muscles 
are  intact,  one  can  understand  why,  on  examining  the  cocainized 
eye  with  the  bright  light  of  an  ophthalmoscope,  there  is  always 
some  contraction  of  the  pupil;  and  why  the  maximum  dilata- 
tion is  to  be  obtained  by  a  mixture  of  cocaine  and  atropine. 

Accommodation  is  not  paralyzed,  as  the  ciliary  muscle  is  not 
affected;   so  cocaine  is  not  available  in  fitting  glasses. 

The  intra-ocular  tension  is  not  increased,  and  in  spite  of  the 
dilatation  of  the  pupil,  which  lasts  only  an  hour  or  two,  may  be 
diminished.  This  effect  is  thought  to  be  due  both  to  the  shrink- 
age of  the  vessels  of  the  eyeball  and  to  the  consequent  diminu- 
tion in  secretion. 

If  one  drop  of  a  4  per  cent,  cocaine  solution  is  dropped  in  the 
eye  every  minute  for  five  minutes,  the  pupil  will  be  fairly  dilated 
in  about  five  minutes  more,  and  the  dilatation  will  last  for  from 
one  to  two  hours.  A  danger  is  the  drying  of  the  cornea,  with 
ulceration  or  clouding. 

In  the  stomach  cocaine  is  locally  anesthetic,  and  will  prevent 
vomiting  from  local  irritants. 

It  is  of  interest  that  in  the  Andes  Mountains  the  natives  chew 
coca  leaves,  and  if  they  have  a  plentiful  supply  of  coca,  can  con- 
tinue to  work  for  several  days  without  food.     They  seem  to  have 


392  PHARMACOLOGY  AND  THERAPEUTICS 

no  feeling  of  hunger  so  long  as  food  is  kept  out  of  their  sight,  but 
the  appetite  returns  if  they  see  or  smell  appetizing  food.  Prob- 
ably there  is  diminished  sensation  in  the  stomach  and  in  the 
mouth,  and  consequent  absence  of  the  effect  on  appetite  of  re- 
flexes from  these  regions,  while  the  psychic  elements  in  the  pro- 
duction of  appetite  (the  sight  or  smell  of  food)  remain  intact. 
The  psychic  stimulation  is  also  probably  a  factor  in  producing 
increased  power  to  work.  It  is  said  that  100,000  000  pounds  of 
the  leaves  are  used  annually  in  South  America,  the  people  chew- 
ing them  with  the  addition  of  a  little  chalk  or  lime. 

These  effects  have  not  been  obtained  in  other  localities,  and 
consequently  have  been  attributed  to  some  unexplained  property 
which  is  confined  to  the  fresh  or  freshly  dried  coca  leaves.  But 
Sollmann  thinks  that  these  effects  have  failed  in  northern  regions 
because  the  drug  has  not  been  tried  in  conditions  of  marked 
hunger  and  fatigue. 

Disagreeable  central  effects  upon  the  alimentary  tract  which 
not  infrequently  follow  the  absorption  of  cocaine,  as  in  spinal 
anesthesia,  are  nausea,  vomiting,  and  diarrhea.  The  cause  of 
these  is  not  known. 

Systemic  Effects. — The  systemic  effects  are  not  made  use  of 
in  therapeutics,  and  may  be  studied  rather  because  of  their  mani- 
festation in  poisoning. 

Heart. — In  perfusing  the  isolated  heart  the  addition  of  co- 
caine does  not  change  the  rate  or  force  of  the  beat,  therefore 
neither  the  muscle  nor  the  accelerator  endings  nor  the  vagus  end- 
ings are  affected.  But  in  the  intact  mammal,  after  a  moment  of 
slowing  from  slight  vagus  center  stimulation,  the  heart  beats 
faster,  and  as  it  does  not  do  so  when  both  accelerators  are  cut, 
the  effect  must  be  stimulation  of  the  accelerator  center.  The 
vagus  endings  retain  their  sensitiveness,  for  even  late  in  the 
poisoning  stimulation  of  a  vagus  nerve  results  in  slowing. 

After  lethal  doses  the  heart  eventually  becomes  weak  and  slow 
from  direct  muscular  depression  (or  perhaps  vagus  stimulation), 
and  death  may  take  place  from  cardiac  failure.  Occasionally,  an 
unexplained,  almost  instant,  collapse  follows  the  absorption  of 
the  drug,  even  when  it  is  used  locally.  In  the  hearts  of  cold- 
blooded animals,  C.  C.  Lieb  has  repeatedly  obtained  auriculo- 
ventricular  dissociation  (heart-block). 

Arteries. — The  vasoconstrictor  center  is  stimulated,  and  blood- 
pressure  rises;  in  severe  poisoning  this  center  is  depressed. 
From  ordinary  amounts  there  is  no  direct  effect  upon  the  arteries, 
such  as  occurs  from  the  local  application,  as  the  drug  is  not  suf- 
ficiently selective  in  its  great  dilution  by  the  blood. 

Crile  calls  attention  to  the  important  fact  that  after  an  in- 


COCA 


393 


travenous  injection  of  cocaine  the  splanchnic  arteries  are  more 
resistant  to  influences  which  usually  cause  their  dilatation,  e.g., 
shock,  handling  the  viscera,  etc. 

Respiration. — The  respiratory  center  is  strongly  stimulated, 
and  the  respiration  is  increased  both  in  rate  and  in  depth.  Death 
is  usually  due  to  respiratory  failure,  though  it  is  not  so  always. 

Cerebrum. — This  is  stimulated  in  much  the  same  way  as  with 
atropine,  even  the  local  use  of  the  drug  being  followed  by  talka- 
tiveness and  cheerfulness,  and  even  delirium  and  cerebral  con- 
vulsions. But  as  an  intellectual  stimulant  it  seems  to  rank  higher 
than  atropine,  for  the  cocaine  jag  is  characterized  by  increased 
intellectual  power  and  self-possession,  in  addition  to  loquacity. 
The  reaction  time  is  shortened,  and  it  is  more  difficult  to  put  and 
keep  an  animal  under  chloroform  or  ether,  i.  e.,  cocaine  antago- 
nizes narcosis. 

The  motor  areas  of  the  brain  are  stimulated,  and  also  the  re- 
flex centers  of  brain  and  cord,  and  there  is  a  tendency  to  motor 
activity  and  restlessness,  so  that  the  patient  wants  to  walk 
about.  A  dog  will  run  amuck,  usually  in  a  circle,  and  quite  in- 
different to  his  surroundings. 

The  ergograph  shows  an  actual  increase  in  muscular  power. 
All  these  things  are  evidences  of  true  central  stimulation,  exactly 
the  opposite  of  the  effect  of  alcohol  or  morphine. 

After  highly  poisonous  doses  the  stimulation  is  followed  by 
depression,  stupor,  cerebral  (not  spinal)  convulsions,  and  coma. 

Medulla. — The  respiratory,  vasoconstrictor,  and  accelerator 
centers  are  stimulated.  Whether  the  vagus  center  is  stimulated 
to  any  great  extent  or  not  is  a  moot  question.  In  poisoning,  the 
thermogenetic  center  in  the  caudate  nucleus  is  affected,  so  that 
the  temperature  may  rise  several  degrees. 

Muscle. — There  is  no  direct  effect,  but  the  motor  areas  are 
stimulated,  so  that  muscular  power  is  increased  and  fatigue  is 
lessened. 

Temperature. — See  under  Medullary  Centers.  The  rise  in 
temperature  has  probably  the  same  explanation  as  that  after 
atropine.     The  temperature  does  not  rise  in  chloralized  animals. 

Excretion. — All,  or  nearly  all,  is  destroyed  in  the  body,  so 
there  are  no  remote  local  effects  in  the  urinary  passages,  as  in  the 
case  of  atropine.  The  urine  is  sometimes  increased,  sometimes 
diminished,  probably  through  changes  in  the  kidney  circulation. 
The  effect  upon  it  is  unimportant. 

Untoward  Effects. — Untoward  effects  following  its  use  for 
anesthesia  are: 

(a)  From  protoplasmic  irritation — cloudiness  or  ulceration  of 
the  cornea;  necrotic  area  or  sterile  abscess  at  the  site  of  injection. 


394  PHARMACOLOGY  AND  THERAPEUTICS 

(b)  After  absorption — (i)  Talkativeness,  excitement,  and 
wakefulness.  (2)  A  profound  narcosis  instead  of  excitement. 
(3)  Nausea,  vomiting,  and  diarrhea,  sometimes  distressing.  (4) 
Sudden  collapse  without  warning. 

A  number  of  cases  are  reported  of  sudden  collapse  in  the 
physician's  office  after  the  local  use  in  nose,  throat,  eye,  and 
urethra.  Great  excitement  has  resulted  from  2  drops  of  a  4  per 
cent,  solution  in  the  eye;  also  conjunctivitis.  One  of  my  cases 
has  twice,  following  cocaine  in  the  eye,  had  a  dilatation  of  the 
arterioles  on  that  side  of  the  face,  so  that  it  was  flushed  and  hot, 
an  effect  which  regularly  follows  sympathetic  paralysis.  Harris 
reports  'death  from  very  small  amounts  in  a  case  with  status 
lymphaticus. 

Acute  Poisoning. — The  central  symptoms  resemble  those 
from  atropine.  They  are  often  observed  after  a  cocaine  debauch 
in  a  habitue.  These  symptoms  are  garrulousness,  restlessness, 
motor  activity,  with  incoordination  like  in  a  drunken  man,  ex- 
citement, hallucinations,  and  delusions;  nausea  and  vomiting; 
rapid  heart  with  raised  blood-pressure;  respiration  quick  and 
deep,  or  even  panting;  pupil  dilated;  throat  dry.  There  are 
frequently  great  anxiety  and  fear  that  death  will  take  place,  and 
anginal  pains  about  the  heart.  Magnan's  sign  is  a  subjective 
sensation  as  of  pimples  or  worms  beneath  the  skin  or  of  vermin  on 
the  skin.  Following  the  excitement  there  are  drowsiness,  stupor, 
coma,  collapse,  cerebral  convulsions,  and  death  from  failure  of 
the  heart  or  respiratory  center.  (See  also  Untoward  Effects.) 
It  may  be  distinguished  from  atropine  poisoning  by  Magnan's 
sign  and  the  reaction  of  the  pupil  to  light,  and  by  the  fact  that 
atropine  checks  sweating,  and  may  be  found  in  the  concentrated 
urine  in  sufficient  amount  to  dilate  the  pupil  of  a  cat's  eye.  Fail- 
ure of  the  heart  to  react  to  pressure  on  the  vagus  in  the  neck 
would  suggest  atropine. 

Treatment. — Because  of  the  marked  anxiety  it  is  of  great  im- 
portance to  reassure  the  patient.  In  the  excitement  stage  an 
ice-bag  to  the  head  and  whisky  or  large  doses  of  bromides  may 
be  supplied,  or  even  inhalations  of  ether.  In  the  collapse  stage 
the  treatment  is  for  collapse,  especial  attention  being  paid  to  the 
respiratory  center.  C.  C.  Lieb  has  repeatedly  checked  cocaine 
heart-block  in  isolated  turtle  hearts  by  caffeine;  but  caffeine 
increases  the  poisoning  of  the  central  nervous  system  and  is 
ordinarily  contraindicated. 

Cocaine  Habit. — The  cocaine  habit  is  quite  common,  espe- 
cially among  nurses,  physicians,  and  druggists,  who  have  easy 
access  to  the  drug,  among  prostitutes,  and  among  the  negroes  of 
the  South.     The  drug  is  taken  as  snuff,  or  is  rubbed  into  the  gums, 


coca  395 

swallowed,  or  injected  hypodermatically.  The  habit  may  be 
diagnosed  by  the  nervousness  and  twitching  in  the  absence  of  the 
dose,  by  the  marks  of  a  hypodermatic. needle,  by  ulceration  in 
the  nose,  with  epistaxis,  if  the  snuff  is  taken,  and  by  the  effects 
of  a  "fake"  dose  of  some  other  drug.  Blue  atrophy  of  the  skin 
at  the  site  of 'the  injections  has  been  reported  by  Gottheil  (191 2). 

When  without  his  .usual  dose  the  habitue  feels  irritable,  de- 
pressed, and  restless,  and  cannot  concentrate  his  attention;  on 
getting  the  dose  his  spirits  brighten  and  he  experiences  a  return  of 
his  mental  and  physical  energies.  By  degrees  he  passes  into 
a  state  of  poor  nutrition,  wasting,  and  anemia,  with  loss  of  appe- 
tite, deranged  digestion,  constipation,  and  insomnia.  He  grad- 
ually reaches  a  state  of  mental  and  moral  weakness,  without 
self-control,  is  easily  depressed,  develops  careless  and  debasing 
habits,  and  lacks  the  inclination  to  work.  He  may  develop 
various  mental  and  nervous  symptoms,  such  as  tremor  of  hands 
and  lips,  irregular  twitching  of  the  shoulder  and  other  muscles, 
queer  sensations  in  the  skin,  and  hallucinations  and  delusions. 
Mania  and  chronic  dementia  and  other  forms  of  insanity  as  re- 
sults of  the  habit  are  reported. 

Treatment. — Isolation,  the  rapid  or  even  the  immediate  with- 
drawal of  the  drug,  with  the  substitution  of  atropine  or  hyoscine, 
and  attention  to  nutrition,  digestion,  bowels,  and  sleep. 

Therapeutics. — The  wine  of  cocoa  is  employed  to  some  extent 
as  a  tonic  and  appetizer  in  run-down  conditions,  or  in  convales- 
cence from  acute  illnesses.  Since  it  has  the  taste  of  wine  and 
contains  Yb  grain  or  more  of  cocaine  and  allied  alkaloids  in  each 
ounce,  it  is  not  surprising  that  a  number  of  cases  of  cocaine 
habit  have  resulted  from  its  use. 

Cocaine  chloride  is  employed  very  extensively  as  an  anes- 
thetic, either  by  application  to  mucous  membranes  in  2  to  10 
per  cent,  solution,  by  hypodermatic  injection  in  0.2  to  4  per  cent, 
solution,  or  by  injection  of  yi  grain  (0.03  gm.)  in  solution  into 
the  spinal  canal. 

In  the  nose,  besides  its  use  as  an  anesthetic,  it  is  employed  to 
shrink  the  tissues  so  as  to  favor  the  passage  of  instruments,  to 
increase  the  view,  to  stop  hemorrhage,  or  to  free  the  nasal  pas- 
sages and  to  lessen  engorgement  in  rhinitis  and  hay-fever.  It  is 
inferior  to  adrenaline  for  these  purposes.  Many  cases  of  cocaine 
habit  can  be  traced  to  the  use  of  sprays  and  powders  in  hay-fever, 
and  not  a  few  to  the  use  of  proprietary  asthma  cures  and  catarrh 
snuffs. 

In  the  throat  it  may  be  sprayed  over  a  hypersensitive  pharynx 
before  examination  with  a  laryngoscope,  or  to  check  a  distress- 


396  PHARMACOLOGY  AND  THERAPEUTICS 

ing  dry  cough,  or  in  tuberculous  laryngitis  to  abolish  pain  and 
permit  the  swallowing  of  food. 

In  affections  of  the  esophagus  (ulcer,  cancer,  esophagitis, 
spasm,  cardiospasm)  cocaine  solution  may  be  swallowed  just  be- 
fore eating,  to  lessen  the  pain  and  spasmodic  contraction  which 
results  from  the  passage  of  food.  A  10  per  cent,  solution  is 
applied  to  the  pharynx  and  larynx  in  direct  laryngoscopy  or 
esophagoscopy  to  prevent  pain  and  shock. 

In  the  stomach  it  is  employed  to  allay  pain,  nausea,  and  vom- 
iting; in  the  eye,  as  anesthetic  for  operations  and  the  removal  of 
foreign  bodies,  and  as  a  transient  pupil-dilator  to  facilitate  ex- 
amination of  the  internal  eye;  in  the  urethra,  to  allay  spasm  and 
permit  the  passage  of  instruments;  at  the  anus,  in  ulcer  or  fis- 
sure, to  allow  a  painless  examination  or  painless  defecation;  on 
the  vulva,  to  overcome  intractable  itching,  and  in  the  entrance  to 
the  vagina  in  vaginismus.  In  irritable  rectum  or  anus  it  may  be 
employed  in  ointment  or  suppository  form. 

In  the  external  ear  the  aqueous  solution  is  not  absorbed,  but 
some  anesthesia  may  be  obtained  from  the  pure  alkaloid  dissolved 
in  aniline  oil.  It  is  reported  that  a  10  per  cent,  solution  in  ether 
will  be  absorbed. 

When  cocaine  is  used  hypodermatically,  it  is  not  injected 
deeply  like  other  drugs  to  hasten  absorption,  but  is  placed  im- 
mediately beneath  the  epidermis.  The  addition  of  epinephrine 
lessens  the  systemic  and  prolongs  the  local  effects,  and  checks 
hemorrhage;  so  in  this  admixture  it  has  recently  come  into  ex- 
tensive use  for  quite  large  operations,  as  amputation  of  a  limb 
or  laparotomy.  It  does  not,  however,  abolish  the  perception  of 
the  patient  or  produce  full  muscular  relaxation.  In  major  opera- 
tions under  general  anesthesia  Crile  and  others  are  attempting 
to  lessen  shock  by  cocainizing  the  operative  area  in  advance  of 
cutting.  Allen  Starr  uses  cocaine  hypodermatically  as  a  diag- 
nostic agent  in  painful  tic,  the  drug  being  injected  at  the  site  of 
that  branch  of  the  fifth  nerve  which  supplies  the  painful  area. 
If  the  pain  disappears,  the  lesion  is  peripheral;  if  not,  it  is  central. 

Spinal  analgesia  with  cocaine  or  one  of  its  relatives  may  be 
employed  for  operations  about  the  perineum  and  lower  extremi- 
ties when  a  general  anesthetic  is  contraindicated,  as  in  severe 
diabetes  and  severe  nephritis.  It  has  also  been  used  to  a  slight 
extent  in  obstetrics.  A  very  important  use  of  it  is  to  prevent 
shock  in  severe  traumatism  of  the  lower  extremities.  Its  value 
for  operations  is  limited  for  the  following  reasons:  (1)  The  extent 
of  the  anesthesia  is  beyond  the  control  of  the  anesthetist,  in  some 
cases  the  whole  body,  even  the  head  and  face,  being  affected. 
(2)  There  is  frequently  vomiting  and  diarrhea  and  excitement, 


COCAINE    SUBSTITUTES 


397 


effects  which  may  persist  for  hours.  (3)  The  patient  remains  con- 
scious, and  is  made  keenly  alert  by  the  drug.  (4)  There  is  little 
or  no  muscular  relaxation.  (5)  Cocaine  collapse  sometimes  oc- 
curs.    A  number  of  deaths  are  reported. 

Systemically ,  cocaine  is  not  ordinarily  employed  at  all,  but, 
if  other  remedies  are  not  at  hand,  it  may  be  used  as  a  central 
stimulant  in  collapse  from  narcotic  drugs. 

Intravenous  Injection  of  Cocaine. — A  method  of  producing 
local  anesthesia  by  injecting  cocaine  into  the  veins  has  been  more 
or  less  used  (Bier's  vein  anesthesia),  a  tourniquet  above  and  be- 
low the  area  to  be  anesthetized  preventing  the  loss  of  cocaine  and 
causing  the  localized  action.     A  danger  is  clotting  in  the  vein. 

Ritter's  (1909)  experiments  with  dogs,  in  which  he  produced 
general  anesthesia  by  an  intravenous  of  a  1  to  5  per  cent,  solu- 
tion, has  not  been  followed  by  any  extensive  use  in  man.  Harri- 
son (191 1)  reports  the  effects  on  himself  of  5  grains  (0.3  gm.)  of 
cocaine  chloride  in  2  per  cent,  solution  introduced  intravenously. 
Cerebration  was  normal  except  for  a  restless  inability  to  keep 
the  mind  long  on  one  subject.  Motor  power  was  unimpaired. 
There  were  dizziness  and  palpitation.  There  was  marked  anal- 
gesia everywhere,  though  slight  twinges  of  pain  were  felt  on  mak- 
ing a  ^4-inch  incision  through  the  skin.  Two  hours  later  there 
was  still  a  slight  impairment  of  feeling.  The  experimenter  says 
that  the  results  are  not  good  enough  to  justify  this  use  of  cocaine. 

COCAINE   SUBSTITUTES 
The  drawbacks  in  the  use  of  cocaine  are: 

1.  Its  general  poisonous  action. 

2.  The  frequency  of  undesirable  idiosyncrasy  to  it. 

3.  Its  decomposition  at  boiling  temperature,  which  prevents 
effective  sterilization. 

4.  Its  poor  keeping  qualities  in  solution. 

5.  Its  tendency  to  vicious  habit  formation. 

Because  of  these  alleged  drawbacks  to  the  use  of  cocaine,  a 
number  of  other  local  anesthetics  have  been  brought  forward  as 
cocaine  substitutes.  Of  these  the  following  are  closely  related 
chemically,  and  are  employed  in  the  same  strength  as  cocaine : 

Eucaine,  beta-eucaine  chloride  or  lactate,  trimethyl-benzoxy- 
piperidine,  which  is  irritant  locally,  but  may  be  boiled  without 
harm,  does  not  constrict  the  arterioles,  and  has  very  slight  effect 
upon  the  pupil  and  accommodation.  The  chloride  is  soluble  in 
30  parts  of  water,  and  the  lactate  in  20  parts. 

Stovaine,  di-methyl-amino-benzoyi  pentanol  chloride,  which 
is  soluble  in  its  own  weight  of  water,  is  more  irritant  locally,  di- 
lates the  arterioles  on  local  application,  and  in  spinal  analgesia 


398  PHARMACOLOGY  AND   THERAPEUTICS 

induces  muscular  relaxation.  It  is  too  irritant  for  use  in  the  eye, 
and  has  shown  a  greater  tendency  than  cocaine  to  produce  local 
gangrene. 

Alypine,  benzoyl-tetramethyl-diamino-ethyl-isopropylic  alco- 
hol chloride,  readily  soluble  in  water.  Its  solutions  will  not 
stand  boiling.  It  dilates  the  arterioles,  and  has  no  effect  on  either 
pupil  or  intra-ocular  tension. 

Novocaine,  para-amino-benzoyl-diethyl-amino-ethanol  chlo- 
ride, soluble  in  its  own  weight  of  water,  and  not  decomposed 
by  boiling,  and  has  no  effect  upon  the  arterioles.  Schley  found 
that  large  doses  administered  to  guinea-pigs  produced  practically 
the  same  poisonous  symptoms  as  cocaine,  but  it  required  about 
six  times  as  much  of  the  novocaine.  As  it  is  not  absorbed  readily 
by  mucous  membranes  or  the  eye,  it  must  be  used  hypodermati- 
cally.  To  prevent  shock,  Crile  uses  a  solution  of  1  :  400  to  anes- 
thetize the  field  of  operation  in  advance  of  cutting. 

Tropacocaine,  the  benzoyl  ester  of  pseudo-tropine  chloride, 
is  more  irritant  locally,  and  does  not  dilate  the  pupil  or  affect 
the  arterioles.     Its  solutions  can  be  boiled. 

These  drugs  are  all  chemically  related  to  cocaine.  They  are 
found  to  be  less  irritating  to  the  tissues  and  less  destructive  if 
dissolved  in  normal  saline  rather  than  pure  water.  They  are 
all  prompt  in  producing  anesthesia,  and  their  effects  last  only 
from  fifteen  minutes  to  half  an  hour;  but  they  all  maintain  anes- 
thesia for  a  much  longer  period  if  used  with  a  small  amount  of 
epinephrine,  the  anesthesia  being  a  little  slower  in  coming  on. 
The  epinephrine  acts  by  constricting  the  arterioles  so  that  the 
drug  is  not  carried  away  so  rapidly  by  the  blood-stream;  a 
further  advantage  is  that,  by  the  blanched  area,  it  shows  exactly 
where  the  drug  has  been  injected. 

SOME  OTHER  LOCAL  ANESTHETICS  NOT    USED    HYPODERMAT- 

ICALLY 

Orthoform,  methyl-para-amido-meta-oxybenzoic  ester,  is  ap- 
plied as  a  powder  to  painful  ulcers,  or  in  ointment  form  to 
projecting  hemorrhoids  or  to  the  vulva  in  pruritus;  or  is  used  in 
suppositories  in  anal  fissure  or  ulcer,  or  in  the  form  of  lozenges  to 
be  dissolved  in  the  mouth  to  overcome  dry  cough,  or  in  tubercu- 
lous laryngitis  to  permit  swallowing.  It  may  be  taken  inter- 
nally for  ulcer  of  the  stomach.  Dose,  5  grains  (0.3  gm.)  in 
suppository,  lozenge,  capsule,  or  powder.  A  5  or  10  per  cent,  oint- 
ment is  also  employed.  The  author  has  seen  a  spreading  der- 
matitis of  the  fingers  and  hands  after  the  use  of  an  orthoform 
ointment.  It  occurred  twice  in  the  same  person  and  was  doubt- 
less due  to  idiosyncrasy. 


OTHER  ANESTHETICS  NOT  USED  HYPODERMATICALLY   399 

Anesthesin,  the  ethyl  ester  of  para-amido-benzoic  acid,  has  the 
same  uses  and  dosage  as  orthoform.  It  is  slightly  soluble  in 
water,  and  more  readily  so  in  alcohol  and  the  oils. 

Propaesin,  para-amido-benzoic-acid-propyl  ester  is  a  crystal- 
line powder,  slightly  soluble  in  water  and  moderately  so  in  al- 
cohol. It  is  used  in  the  same  way  as  the  last  named,  in  doses  of 
5  grains  (0.3  gm.)  or  in  10  per  cent,  ointment.  DipropcEsin  is 
a  combination  of  one  molecule  of  urea  with  two  of  propaesin. 
It  is  anesthetic  in  an  alkaline  medium. 

Chloretone,  chlorbutanol,  is  sometimes  employed  in  the 
same  way  (see  under  Hypnotics),  in  powder,  tablets,  spray,  etc., 
as  a  local  anesthetic. 

Holocaine,  para-diethoxy-ethenyl-diphenyl-amidin  chloride, 
is  very  soluble  in  water,  but  more  irritant  and  more  toxic  than 
cocaine.  In  forty-five  seconds  a  i  per  cent,  solution  produces 
an  anesthesia  of  the  eye  which  lasts  ten  or  fifteen  minutes,  with- 
out any  effect  on  pupil,  accommodation,  intra-ocular  tension, 
or  the  arterioles. 

Dionine,  di-ethyl  morphine  chloride,  is  soluble  in  7  parts  of 
water,  and  is  used  in  5  per  cent,  solution  to  dilate  the  pupil,  to 
lessen  intra-ocular  tension,  and  to  abolish  pain  in  the  eye. 
Snyder  prefers  it  to  eserine  in  glaucoma.  At  first  it  causes  great 
irritation  and  even  chemosis,  but  this  soon  disappears.  Its  sys- 
temic effect  is  similar  to  that  of  codeine.     (See  Morphine.) 

Yohimbine  is  an  alkaloid  yielded  by  a  tree  of  the  Apocynacece 
of  German  West  Africa.  Its  solutions  decompose  on  boiling  and 
deteriorate  on  keeping.  It  is  less  anesthetic  than  cocaine  and 
dilates  the  pupil,  but  it  so  strongly  dilates  the  vessels  that  to 
prevent  hyperemia  a  2  per  cent,  solution  requires  to  be  mixed 
with  an  equal  quantity  of  epinephrine  ^solution. 

Taken  by  mouth,  yohimbine  is  said  to  cause  a  dilatation  of 
the  cutaneous  vessels,  to  stimulate  the  lower  part  of  the  spinal 
cord,  to  increase  sexuality,  and  to  induce  erections  of  the  penis 
which  may  or  may  not  be  accompanied  by  sexual  desire.  Dose, 
yi  grain  (0,008  gm.),  or  in  2  per  cent,  solution  hypodermatically 
8  minims  (0.5  c.c).  A  number  of  veterinary  writers  have  re- 
ported aphrodisiac  effects  in  cows,  pigs,  and  horses. 

Schleich's  infiltration  anesthesia  was  famous  at  one  time. 
He  used  solutions  of  the  chlorides  of  morphine  and  cocaine  in 
three  different  strengths  in  0.2  per  cent,  solution  of  sodium  chlo- 
ride. The  strongest  of  his  solutions  contained  0.2  per  cent,  of 
cocaine  and  0.025  per  cent,  of  morphine. 

Other  local  anesthetics  are  the  ethyl  chloride  spray,  which 
freezes  the  part,  and  is  only  momentary  in  its  effects,  and  phenol, 


400  PHARMACOLOGY   AND   THERAPEUTICS 

a  5  per  cent,  solution  of  which,  kept  in  contact  with  the  part,  will 
slowly  numb  and  anesthetize. 

Eriodictyon  (yerba  santa)  is  an  astringent,  resinous,  bitter 
drug,  of  which  the  fluidextract  is  official;  dose,  30  minims  (2  c.c). 
It  possesses  the  peculiar  local  action  of  acting  on  the  taste-buds 
to  abolish  the  taste  for  bitter,  though  not  that  for  sweet,  salt,  or 
sour.  If  the  mouth  is  rinsed  with  a  little  of  the  fluidextract  di- 
luted with  water,  a  dose  of  quinine  or  strychnine  taken  three  or 
four  minutes  later  gives  scarcely  any  bitter  taste.  It  is  some- 
times made  into  a  syrup  and  used  as  a  vehicle  for  the  administra- 
tion of  quinine  to  children ;  but  in  such  admixture  it  has  no  time 
to  act  on  the  taste-buds,  and  really  lessens  the  bitterness  of  the 
quinine  salt  by  changing  it  to  the  tannate,  an  almost  insoluble 
and  therefore  almost  tasteless  salt. 

MAGNESIUM  SULPHATE  (EPSOM  SALT) 
In  1899  Meltzer  noted  paralysis  in  a  rabbit  from  the  intra- 
cerebral injection  of  magnesium  sulphate,  and  in  1905  was 
joined  by  Auer  in  an  investigation  of  this  action.  They  found 
that  a  25  per  cent,  solution  applied  to  a  nerve- trunk  completely 
blocked  both  sensory  and  motor  impulses;  that  on  subcutaneous 
injection  there  was  complete  anesthesia  with  muscular  relaxa- 
tion lasting  for  two  or  three  hours  and  without  any  cathartic 
effect,  and  that  the  injection  into  the  spinal  canal  was  followed 
by  sensory  and  motor  paralysis  and  profound  narcosis.  The 
paralysis  began  in  the  hind  legs  and  spread  upward  until  it  in- 
volved the  anterior  extremities.  With  lethal  doses  the  blood- 
pressure  was  but  little  affected,  and  death  was  due  to  respira- 
tory paralysis. 

In  one  experiment  on  a  monkey  a  lethal  dose  was  given  in- 
traspinally.  Respiration  failed,  but  as  the  heart  continued  beat- 
ing, artificial  respiration  was  instituted.  After  seven  hours  the 
artificial  respiration  was  stopped,  and  the  animal  was  found  to 
be  still  incapable  of  spontaneous  respiration.  After  seven  hours 
more  the  artificial  respiration  was  again  stopped,  and  then  the 
animal  continued  to  breathe  without  aid.  During  all  the  period 
of  respiratory  paralysis  the  heart's  action  continued  good  and 
there  was  evidently  no  cardiac  or  vasoconstrictor  depression. 
Meltzer  and  Lucus  found  that  after  its  subcutaneous  injection 
the  drug  was  eliminated  by  the  kidneys,  and  that  when  the  kid- 
neys were  impaired,  it  was  twice  as  poisonous,  and  might  have  a 
cumulative  action.  Canestro  (1910)  found  that  the  addition  of 
a  small  amount  of  adrenaline  made  it  less  toxic  to  the  respiratory 
center.     Hyndman  and  Mitchener  (1910)  found  it  no  more  de- 


MAGNESIUM   SULPHATE  (EPSOM    SALT)  401 

pressing  to  the  motor  area  of  the  brain  than  ether,  as  tested  by 
electric  stimulation.   f 

Following  these  experiments  the  drug  has  been  used  "intra- 
spinally"  in  human  cases,  J.  A.  Blake,  for  example,  having  em- 
ployed it  in  two  cases  for  operative  anesthesia,  in  one  case  for 
tetanus,  and  in  one  case  for  convulsions  wrongly  supposed  to  be 
due  to  tetanus;  Markoe  in  i  fatal  case  of  tetanus;  Logan  in  2 
fatal  cases  of  tetanus;  and  Willy  Meyer,  Haubold,  Fraenkel, 
and  others  in  various  cases.  A  number  of  cases  of  tetanus  suc- 
cessfully treated  have  been  reported,  and  Johnson  and  Phillips, 
independently,  report  it  more  effective  than  the  serum.  The 
dose  is  1  c.c.  of  25  per  cent,  solution  for  each  25  pounds  of  body 
weight. 

As  an  anesthetic  it  has  proved  very  uncertain:  in  some  cases 
anesthesia  did  not  result,  in  some  it  appeared  in  fifteen 
minutes,  in  some  only  after  two  or  three  hours.  In  a  number 
of  the  patients  there  were  general  anesthesia  and  muscular 
relaxation,  with  a  profound  narcosis  from  which  the  patient  could 
not  be  aroused  for  from  twenty-four  to  forty-eight  hours.  Four- 
teen cases  collected  by  Blake  gave  the  following  data:  In  8 
the  anesthesia  was  incomplete,  but  was  made  complete  with  very 
little  chloroform  or  ether.  Coma  lasting  one  to  nineteen  hours 
occurred  in  6.  Muscular  paralysis  was  complete  in  twelve  and 
persisted  for  twenty-four  hours  in  6.  Retention  of  urine  for 
twenty-four  hours  or  more  occurred  in  12 ;  marked  vomiting  in  3. 
Even  with  the  most  profound  anesthetic  effects  the  heart's  action 
was  regular;  and,  when  taken,  the  blood-pressure  was  not  low- 
ered. In  three  cases  the  effect  of  the  drug  was  checked  by  wash- 
ing out  the  spinal  canal  with  successive  quantities  of  salt  solu- 
tion, as  suggested  by  Meltzer. 

Dawbarn,  in  using  spinal  analgesia  to  block  afferent  impulses 
in  traumatic  shock,  found,  as  Wainwright  did,  that  when  the 
effect  of  a  rapidly  acting  local  anesthetic  wears  off,  the  shock 
may  reappear  and  the  patient  die,  death  being  merely  postponed 
an  hour  or  two.  In  two  cases  he  employed  a  solution  of  mag- 
nesium sulphate  with  tropacocaine,  and  found  that  in  both  the 
nerve-blocking  began  quickly  and  continued  for  from  twenty-four 
to  forty-eight  hours,  i.  e.,  the  tropacocaine  began  the  anesthesia 
early,  and  the  magnesium  sulphate  continued  it.  Injected  along 
the  course  of  the  nerves  it  also  anesthetizes. 

Therapeutics. — Owing  to  its  prolonged  action  magnesium 
sulphate,  used  intraspinally,  would  seem  to  be  particularly  valu- 
able and  safe  in  the  convulsions  of  tetanus,  strychnine  poisoning, 
and  eclampsia,  and  in  preventing  shock  from  severe  traumatism. 
For  general  use  in  operations  it  is  too  uncertain,  and  its  action 
26 


402  PHARMACOLOGY  AND  THERAPEUTICS 

likely  to  be  too  prolonged.  It  has  been  suggested  as  a  possible 
measure  of  relief  in  refractory  sciatica. 

Corrado  (1910)  was  able,  with  a  7.3  per  cent,  solution  given 
subcutaneously,  to  check  the  tetanic  symptoms  following  para- 
thyroidectomy. Paterson  (1910)  cured  tetanus  with  a  10  per 
cent,  solution  subcutaneously. 

Recently  a  saturated  solution  of  magnesium  sulphate  (it  is 
soluble  in  0.85  part  of  water)  has  been  much  employed  in  the 
form  of  a  wet  compress  as  a  local  application  to  reduce  the  pain 
in  neuralgia,  neuritis,  dermatitis,  and  burns.  Tucker  (191 1)  re- 
ports good  results  in  epididymitis,  arthritis,  cellulitis,  and  ery- 
sipelas.    (For  magnesium  poisoning  see  Saline  Cathartics.) 

Intravenous  Local  Anesthesia. — This  method,  introduced  by 
Bier,  gives  complete  anesthesia  of  a  limb.  The  blood  is  squeezed 
out  of  the  veins  between  two  Esmarch  bandages,  and  a  0.5  per 
cent,  novocaine  solution  injected  into  a  vein.  The  solution 
reaches  all  parts  of  the  segment,  and  produces  complete  anes- 
thesia of  the  segment  in  five  minutes,  so  that  even  an  amputation 
may  be  performed  without  pain.  In  an  adult  50  to  100  c.c.  of 
the  solution  are  required  for  the  arm,  and  somewhat  more  for 
the  leg. 


Some  Peripheral  Depressants  Not  Of  Great 
Medicinal  Importance 

1.  hydrocyanic  acid  and  cyanides 

Preparations. — Diluted  hydrocyanic  acid,  HCN,  a  2  per  cent, 
solution;  dose,  1  minim  (0.06  c.c).  It  rapidly  deteriorates  on 
keeping.  Undiluted  hydrocyanic  (prussic)  acid  is  not  employed 
in  medicine. 

Potassium  cyanide,  KCN;   dose,  y^  grain  (0.0 1  gm.). 

In  addition,  hydrocyanic  acid  is  present  in  preparations  of 
wild-cherry  bark  (Prunus  virginiana) ,  the  oil  of  bitter  almond 
(Amygdala  amara),  and  cherry-laurel  leaves  (Laurocerasus) .  In 
these  it  does  not  occur  in  the  crude  drugs,  but  is  developed  in  the 
presence  of  water  by  the  action  of  the  ferment  emulsin  on  the 
glucoside  amygdalin,  both  of  which  are  present.  (For  the  re- 
action, see  Part  I,  Glucosides.)  The  official  oil  of  bitter  almond 
contains  2  to  4  per  cent,  hydrocyanic  acid  and  85  per  cent, 
benzaldehyde ;  dose,  1  minim  (0.06  c.c).  The  preparations  of 
these  are: 

Infusion  of  wild  cherry,  4  per  cent.;  dose,  2  ounces  (60  c.c). 
Syrup  of  wild  cherry,  15  per  cent.;   dose,  1  dram  (4  c.c). 
Fluidextract  of  wild  cherry;   dose,  30  minims  (2  c.c). 


HYDROCYANIC    ACID    AND    CYANIDES  403 

Bitter  almond  water  (aqua  amygdalae  amarae),  0.1  per  cent.; 
dose,  1  dram  (4  ex.). 

Spirit  of  bitter  almond,  1  per  cent.,  3  minims  (0.2  ex.). 

Action. — Cyanides  are  general  protoplasmic  poisons,  highly 
toxic  to  all  living  things,  and  antagonistic  to  the  action  of  the 
body  ferments.  Locally,  they  tend  to  depress  the  ends  of  the 
sensory  nerves. 

Poisoning. — Large  doses  so  affect  the  protoplasm  of  the  body 
that  it  is  unable  to  absorb  oxygen  from  the  blood.  As  a  conse- 
quence, the  venous  blood  is  like  the  arterial  blood,  i.  e.,  red  and 
oxygenated.  This  is,  so  far  as  we  know,  due  to  inhibition  of  the 
activity  of  the  oxidases  (oxidizing  ferments),  through  whose 
action  the  oxygen  of  the  blood  is  utilized  in  the  cells.  This 
property  of  cyanides  has  been  established  by  Richards  as  of 
value  in  the  study  of  the  action  of  certain  oxidizable  poisons. 

After  a  toxic  dose  of  cyanide  there  is  a  passing  stimulation  of 
the  vagus,  vasoconstrictor,  and  respiratory  centers,  followed  by 
marked  depression  of  these.  There  are  widely  dilated  pupils, 
and  vomiting  from  stimulation  of  the  pupil-dilating  and  vomiting 
centers,  then  convulsions,  probably  of  medullary  origin,  collapse, 
and  death  from  failure  of  the  respiration.  Very  large  doses  taken 
when  the  stomach  is  empty  are  followed  almost  immediately  by 
a  few  convulsive  movements  and  death.  The  fatal  dose  is  vari- 
able because  of  differences  in  the  strength  of  preparations.  An 
amount  of  dilution  equivalent  to  about  1  minim  of  pure  hydro- 
cyanic acid,  or  2]/2  grains  (0.16  gm.)  of  potassium  cyanide,  is 
reckoned  to  be  a  lethal  dose  (Taylor).  For  an  elephant  in  Cen- 
tral Park  it  required  9  ounces  (180  gm.)  of  potassium  cyanide  to 
produce  death.  The  poison  may  be  detected  by  the  characteris- 
tic odor,  which  is  perceptible  in  the  mouth  or  the  emptied 
bottle,  or  at  postmortem  on  opening  the  body. 

Treatment. — Prompt  emptying  of  the  stomach  and  the  ad- 
ministration by  mouth  of  oxidizing  antidotes,  such  as  hydrogen 
peroxide,  potassium  permanganate,  or,  perhaps,  much  better, 
freshly  prepared  ferric  hydroxide  (the  arsenic  antidote).  Intra- 
venously 1  per  cent,  sodium  hyposulphite,  and  0.5  per  cent,  co- 
baltous  nitrate  have  been  recommended.  In  addition,  artificial 
respiration  and  the  general  treatment  for  collapse  are  indicated. 

Therapeutics. — It  has  been  employed  locally  to  allay  itching 
and  to  stop  nausea  and  vomiting.  It  is  also  used  to  check  cough. 
There  is  no  evidence  to  justify  its  employment  for  these  purposes, 
and  it  would  seem  that  the  medicinal  use  of  hydrocyanic  acid  or 
potassium  cyanide  might  with  advantage  be  abandoned. 

The  syrup  of  wild  cherry  is  much  used  as  a  flavor  in  cough 


404  PHARMACOLOGY  AND  THERAPEUTICS 

mixtures.     Cherry-laurel  water  and  the  water  and  spirit  of  bitter 
almond  are  used  as  flavors. 

CURARE 

Curare,  containing  the  alkaloid  curarine,  is  a  South  American 
arrow-poison.  It  is  probably  obtained  from  a  species  of  Strych- 
nos,  the  genus  to  which  the  strychnine-yielding  plants  belong. 
Its  essential  action  is  to  paralyze  the  motor  end-plates  in  striped 
muscles,  and  for  this  purpose  it  is  largely  used  in  physiologic  and 
pharmacologic  laboratories.  It  has  been  used  in  certain  convul- 
sive or  spasmodic  conditions  of  striped  muscle,  but  its  dosage  is 
very  uncertain,  and  its  tendency  to  paralyze  the  respiratory 
muscles  is  marked,  hence  it  is  too  dangerous. 

CONIUM 
Conium,  or  "poison  hemlock"  (not  "hemlock"),  contains 
the  volatile  liquid  alkaloid  coniine.  The  fluidextract  is  official; 
dose,  3  minims  (0.13  c.c).  There  is  some  medullary  depression 
and  slight  sensory  depression,  but  the  main  effect  is  a  curare-like 
but  mild  depression  of  the  motor  end-plates.  For  this  it  has  been 
used  somewhat  in  certain  spasmodic  nervous  affections,  such  as 
chorea  and  whooping-cough,  but  has  been  found  of  little  value. 
It  was  by  conium  that  Socrates,  the  philosopher,  was  put  to 
death;  and  as  his  mind  remained  clear  until  near  the  end,  he 
wrote  a  description  of  his  condition.  There  was  paralysis  with 
slight  numbness,  beginning  in  the  toes  and  gradually  ascending 
until  it  involved  the  trunk.  Death  from  conium  is  due  to  re- 
spiratory paralysis,  either  of  the  respiratory  center  or  of  the  ter- 
minals in  the  respiratory  muscles. 

GELSEMIUM 

Gelsemium,  yellow  jasmine,  has  as  its  active  principle  the 
alkaloid,  gelseminine.  The  fluidextract,  dose,  1  minim  (0.06 
c.c),  and  the  10  per  cent,  tincture,  dose,  10  minims  (0.6  c.c),  are 
official. 

Peripherally  it  acts  like  conium,  but  centrally  is  more  de- 
pressing. It  is  somewhat  analgesic,  and  has  an  atropine  action 
on  the  pupil  and  accommodation.  Therapeutically,  it  has  been 
employed  with  reputed  good  effects  in  refractory  trifacial  neu- 
ralgia, but  just  how  it  checks  the  neuralgic  pain  has  not  been 
explained. 

SPARTEINE  SULPHATE 

Sparteine  sulphate,  dose,  1  grain  (0.06  gm.),  is  the  sulphate 
of  an  alkaloid  obtained  from  Scoparius,  or  broom.     It  slows  and 


TOBACCO  405 

weakens  the  heart  by  stimulating  the  ganglia  on  the  vagus  nerve 
and  by  directly  depressing  the  heart  muscle;  it  also  slightly  stim- 
ulates the  ganglia  of  the  vasoconstrictor  nerves.  Sparteine  was 
formerly  believed  to  have  a  digitalis  action,  but  by  blood-pres- 
sure experiments  in  the  laboratory  this  is  not  found  to  be  the 
case. 

It  may  be  used  to  quiet  an  overacting  heart,  and  on  the  theory 
that  it  depresses  the  ganglia  of  bronchoconstrictor  nerves  may  be 
employed  in  spasmodic  asthma. 

LOBELIA 

Lobelia,  Indian  tobacco,  the  active  principle  of  which  is  the 
volatile  liquid  alkaloid  lobeline,  resembles  nicotine  or  real  to- 
bacco in  its  action.  Its  chief  use  is  in  spasmodic  asthma,  to 
depress  the  bronchomotor  nerve-endings  or  their  ganglia.  Small 
doses  taken  repeatedly  cause  an  unexplained  persistent  increase 
in  the  frequency  of  the  heart-beat.  The  fluidextract,  dose,  2 
minims  (0.13  c.c),  and  the  10  per  cent,  tincture,  dose,  20  minims 
(1.3  c.c),  are  official.  The  leaves  are  a  constituent  of  some  of  the 
proprietary  asthma  powders,  which  are  used  for  burning,  the 
smoke  being  inhaled.  They  are  sometimes  made  into  cigars  or 
cigarettes  with  stramonium,  cubebs,  or  tobacco,  and  these  smoked 
during  an  asthmatic  attack.  Lobelia  has  also  been  employed  as 
an  emetic,  the  dose  required  being  four  times  that  mentioned 
above. 

TOBACCO    (TABACUM) 

Tobacco  is  the  leaves  of  Nicotiana  tabacum  (Fam.  Solanacece) , 
subjected  to  a  process  of  fermentation  to  remove  certain  proteins 
and  fats  that  would  make  the  smoke  disagreeable,  and  then  to 
another  process  of  fermentation  by  which  25  or  30  per  cent,  of  the 
nicotine  is  lost  and  the  aroma  developed.  The  chief  constituents 
of  the  cured  leaves  (not  the  smoke)  are  the  volatile  liquid  alkaloid, 
nicotine,  some  related  alkaloids,  and  a  volatile  oil  to  which  most 
of  the  aroma  is  due.  (For  the  constituents  of  the  smoke  see 
below.)  The  Havana  tobacco  is  noted  for  its  delicate  aroma,  and 
usually  contains  only  1  to  3  per  cent,  of  nicotine;  while  some  of 
the  Virginia  and  French  tobaccos  may  yield  as  much  as  6  or  7  per 
cent.  An  examination  of  Virginia  tobaccos  by  the  Virginia 
Agricultural  Experiment  Station  in  1898  showed  1.68  to  6.17  per 
cent,  of  nicotine.  Turkish  tobacco  comes  from  Nicotiana  Rustica, 
and  contains  about  2.5  per  cent,  of  nicotine  (Kew  Bulletin). 

The  cured  tobacco  is  used  for  smoking;  or,  mixed  with  molas- 
ses, extract  of  licorice,  and  other  flavoring  materials,  is  used 
for  chewing  (chewing- tobacco).    When  powdered,  also  sometimes 


406  PHARMACOLOGY   AND   THERAPEUTICS 

scented  and  flavored,  it  constitutes  snuff,  which  is  used  by  snuff- 
ing into  the  nose  or  rubbing  upon  the  gums. 

For  smoking,  tobacco  is  burned  in  a  pipe,  or  in  the  form  of 
cigarette  or  cigar,  the  smoke  being  drawn  through  the  tobacco 
into  the  mouth,  or  sometimes  "inhaled,"  that  is,  drawn  into 
the  lungs.  A  method  of  drawing  the  smoke  through  water 
or  rose-water,  as  in  the  "hookah,"  is  in  vogue  in  eastern  countries. 
It  is  said  that  this  takes  out  about  half  the  nicotine  and  cools  the 
smoke.  The  smoke  contains  nicotine,  pyridine,  quinoline,  hydro- 
cyanic acid,  irritant  aldehyds,  ammonia,  carbon  monoxide,  and 
some  volatile  oil.  How  much  of  the  nicotine  of  tobacco  is  de- 
stroyed in  the  smoking  is  a  question,  some  investigators  rinding 
that  only  one-fifth  is  recoverable  from  the  smoke,  while  others 
report  the  recovery  of  as  much  as  four-fifths.  Lehmann  (191 2) 
has  shown  that  the  hydrocyanic  acid  is  not  a  factor  in  the  tobacco 
effects;  but  the  investigations  of  the  London  Lancet  (191 2)  point 
to  furfurol  aldehyd  and  other  aldehyds  as  harmful  constituents. 
Furfurol  is  a  constituent  of  the  fusel  oil  of  alcohol,  and  the  Lancet 
experiments  show  that  a  single  cigarette  may  contain  as  much  of 
it  as  two  ounces  of  whisky.  Furfurol  is  practically  absent  from 
the  smoke  of  Turkish  cigarettes. 

In  medicine,  tobacco  has  been  employed  externally  in  the  form 
of  a  poultice,  and  internally  as  an  emetic,  and  the  smoke  has  been 
inhaled  in  spasmodic  asthma;  but,  owing  to  its  great  toxicity  and 
to  the  great  difference  in  human  susceptibility  to  its  action,  it  is 
dangerous  as  a  remedy  and  has  been  omitted  from  the  Phar- 
macopoeia. Tobacco  is  still  used  more  or  less  in  asthma,  and  in 
addition  to  stramonium,  lobelia,  or  cubebs,  forms  a  constituent 
of  many  of  the  asthma  cigarettes  and  cigars.  As  its  value  is  so 
limited,  tobacco  is  to  be  considered  chiefly  because  of  the  effects 
of  the  tobacco  habit. 

The  world's  output  has  been  placed  at  2,000,000,000  pounds 
a  year.  In  the  United  States  alone  in  191 1,  according  to  the 
internal  revenue  reports,  the  output  of  manufactured  tobacco  was 
389,865,917  pounds,while  the  cigarettes  numbered  9,828,682,005, 
and  the  cigars,  8,477,892,940.  That  would  be  over  4  pounds  of 
tobacco  and  over  100  cigars  and  100  cigarettes  for  each  inhabitant. 

Pharmacologic  Action  of  Nicotine. —  Nicotine  is  rapidly 
absorbed  from  skin  and  mucous  membranes.  Its  main  action 
is  a  brief  stimulation  of  the  cerebrum,  medulla,  and  cord,  of  the 
ganglia  on  the  vagus  and  sympathetic  nerves,  and  of  the  motor 
end-plates  in  voluntary  muscle,  the  stimulation  being  followed  by 
depression. 

Alimentary  Tract. — The  saliva  is  increased  and  there  may  be 
biting  of  the  tongue  from  the  irritant  nicotine.    Either  from  the 


TOBACCO  407 

local  effect  of  the  swallowed  saliva  or  from  its  systemic  effect 
after  absorption  there  may  be  nausea,  vomiting,  and  increased 
peristalsis  with  diarrhea. 

Circulation. — The  stimulation  of  the  vagus  center  and  ganglia 
results  in  a  slowing  of  the  heart,  and  that  of  the  vasoconstrictor 
centers  and  ganglia  in  a  great  rise  in  blood-pressure;  the  sub- 
sequent depression  shows  in  a  rapid  heart  and  lowered  blood- 
pressure.  From  smoking,  a  preliminary  rise  of  10,  15,  or  even 
25  mm.  Hg  is  not  uncommon  during  the  first  fifteen  or  twenty 
minutes,  but  it  may  be  absent  in  those  who  are  very  tolerant  of 
the  drug.  To  one  who  is  not  habituated,  the  subsequent  fall  in 
pressure  may  result  in  mild  collapse.  A  fall  of  50  mm.  has  been 
noted.  Cannon,  Aub,  and  Binger  (191 2)  have  shown  that  nicotine 
can  cause  increased  activity  of  the  adrenals. 

Respiratory. — This  center  is  also  stimulated,  then  depressed. 
The  bronchial  muscles,  from  stimulation  followed  by  depression 
of  the  ganglia  of  their  motor  nerves,  undergo  a  transient  contrac- 
tion, followed  by  persistent  relaxation;  hence  the  use  of  tobacco 
in  spasmodic  asthma. 

Smooth  muscle  of  all  kinds  is  affected  through  the  ganglia 
of  the  supplying  nerves. 

The  pupil  is  contracted  at  first  and  subsequently  dilated.  This 
is  from  an  effect  on  the  third-nerve  ganglia. 

The  cerebrum  is  only  slightly  stimulated,  and  this  effect  so 
quickly  passes  into  depression  that  the  drug  is  a  true  narcotic  or 
cerebral  sedative.  Tobacco  is  not  an  intellectual  stimulant,  but 
just  the  reverse. 

The  medullary  centers  and  the  reflexes  are  at  first  stimulated, 
then  depressed. 

Toxicology. — The  poisonous  effects  of  tobacco  are  chiefly  due 
to  nicotine.  Two  drops  of  nicotine  placed  on  the  tongue  or 
rubbed  into  the  gums  of  a  small  dog  or  cat  will  produce  death  in 
one  or  two  minutes.  A  large  mastiff  died  almost  instantly  when 
ten  drops  were  placed  on  his  tongue,  and  a  canary  when  one  drop 
was  held  near  its  bill.  In  man  death  has  followed  the  use  of 
tobacco  as  a  poultice,  the  application  of  an  infusion  in  skin 
disease,  the  injection  of  an  infusion  into  the  rectum,  the  plugging 
of  a  wound  with  a  quid  of  tobacco  to  stop  the  bleeding,  etc.  In 
fact,  a  cigar  may  contain  enough  nicotine  to  kill  two  un- 
habituated  adults. 

Acute  nicotine  poisoning  is  frequently  seen  after  the  first  cigar, 
or  when  an  unusually  large  quantity  of  tobacco  is  consumed  in 
a  short  time.  The  symptoms  are  those  of  mild  collapse,  viz., 
pallor  of  the  skin,   sweating,   nausea,   and  perhaps  vomiting, 


408  PHARMACOLOGY  AND  THERAPEUTICS 

diarrhea,  muscular  weakness,  faintness,  dizziness,  and  lowered 
arterial  pressure. 

Treatment. — Fresh  air  and  rest  lying  down,  with  reflex  stimu- 
lants, such  as  whisky,  brandy,  or  aromatic  spirits  of  ammonia. 
More  tobacco  can  be  borne  when  one  drinks  liquor  at  the  same 
time. 

If  the  symptoms  are  severe,  the  treatment  is  that  for  severe 
collapse;  but  this  degree  of  poisoning  is  rare  from  smoking,  as  the 
stomach  symptoms  or  the  mild  collapse  come  on  early  and  check 
the  further  use  of  the  drug.  Were  the  drug  to  manifest  its  symp- 
toms more  slowly,  so  that  a  larger  dose  might  be  consumed  before 
the  smoker  becomes  ill,  many  serious  poisonings  would  result. 

Tolerance  is  readily  established  up  to  a  certain  limit,  which 
differs  widely  with  different  persons,  e.  g.,  the  limit  of  tolerance  for 
one  person  is  a  single  cigar  in  an  evening,  while  another  person 
may  smoke  ten  cigars  in  the  same  time  without  being  upset.  After 
the  use  of  tobacco  has  been  abandoned  for  a  time  the  tolerance 
to  it  is  found  to  have  decreased. 

The  Tobacco  Habit. — As  a  habit  drug,  tobacco  is  peculiar  in 
that  the  effects  desired  are  not  to  be  attributed  in  any  great 
degree  to  its  most  active  constituent,  nicotine.  Indeed,  the  best 
tobaccos  are  not  by  any  means  those  with  the  highest  percentages 
of  the  alkaloid. 

To  the  beginner  in  smoking  the  pleasure  is  sadly  lacking ;  and 
it  is  not  until  the  habit  is  established  that  smoking  becomes  a 
source  of  comfort  and  pleasure.  But  to  the  habitue  tobacco  is 
narcotic,  promoting  the  feelings  of  ease  and  relaxation.  Strangely 
enough,  its  pleasurable  effects  seem  quite  unrelated  to  the  extent 
of  the  physiologic  action,  for  to  most  smokers  there  is  little  sat- 
isfaction from  smoking  in  the  dark  or  from  using  the  tobacco  in 
some  unaccustomed  way,  as  in  a  pipe  instead  of  cigarettes,  or  as 
snuff;  and  the  weak  Havana  tobacco  often  gives  more  pleasure 
than  the  two  or  three  times  as  strong  Virginia  or  Kentucky 
variety.  It  is  a  fact,  also,  that  those  who  have  the  habit  of  inhal- 
ing, and  are,  therefore,  accustomed  to  bringing  the  smoke  in  con- 
tact with  a  large  surface  of  mucous  membrane,  get  little  satis- 
faction, no  matter  how  strong  the  tobacco,  unless  they  inhale  to 
bring  the  smoke  to  the  accustomed  membranes.  The  same  may 
be  said  of  the  use  of  tobacco  in  the  form  of  snuff — smoking  will 
not  satisfy  the  snuff-user. 

Another  noteworthy  fact  is  that  there  is  no  great  physiologic 
demand  for  the  usual  dose  of  nicotine,  so  that  the  habit  of  smok- 
ing can  be  stopped  suddenly  without  any  striking  physiologic 
reaction.  Also,  a  moderate  smoker — one  who  is  accustomed,  say, 
to  one  cigar  after  his  dinner — can  get  along  very  well  without  his 


TOBACCO  409 

smoke,  and  will  have  less  craving  for  it  two  or  three  hours  later 
than  he  had  at  the  usual  time  for  it.  This  is  not  true  of  morphine, 
cocaine,  or  the  other  habit  drugs,  for  which  the  craving  becomes 
worse  and  worse  as  the  deprivation  continues. 

It  is  evident,  then,  that  the  demand  for  tobacco  is  not  so 
much  the  physiologic  demand  of  the  body  for  its  dose  of  nicotine, 
as  it  is  the  psychic  demand  for  the  satisfaction  of  a  habit.  The 
smoker's  pleasure  seems  to  be  derived  largely  from  the  presence 
of  something  in  the  mouth,  from  the  studied  inhalation  and  exha- 
lation, and  from  the  soft  circling  up  of  the  smoke.  The  fact  that 
the  presence  of  something  in  the  mouth  with  rhythmic  motion  of 
the  jaw,  as  in  gum-chewing,  gives  a  pleasure  that  is  similar, 
though  weaker,  places  the  use  of  tobacco  in  a  psychic  habit  class 
with  chewing-gum,  eating  chocolate,  or  perhaps  sucking  a  tooth- 
pick. In  attempting  to  break  the  tobacco  habit  we  take  advan- 
tage of  this  fact  and  advocate  the  chewing  of  gum,  or  of  some  sub- 
stance of  strong  taste,  such  as  gentian  or  lovage,  or  the  eating  of 
candy  at  the  usual  smoking  time. 

That  the  effect  is  not  all  psychic,  however,  is  attested  by  the 
failure  of  any  other  substance  to  give  the  satisfaction  that  tobacco 
does,  either  for  smoking  or  chewing.  Every  one  prefers  to  smoke 
tobacco,  for  example,  rather  than  cabbage  leaves,  though  the 
smoke  of  cured  cabbage  leaves  contains  pyridine  bases.  This 
preference  for  tobacco  may,  however,  be  merely  a  matter  of  the 
greater  delicacy  of  the  tobacco  taste  and  aroma. 

The  method  of  smoking  makes  some  difference.  The  Lancet 
has  shown  that  the  pipe  smoke  contains  the  most  nicotine  and 
the  cigarette  smoke  the  least.  The  pipe  has  the  disadvantage 
that,  owing  to  the  heat  of  the  tobacco  and  the  bowl  of  the  pipe, 
oily  nicotine  and  pyridine  substances  tend  to  distil  into  the  smoke 
without  combustion.  Some  of  these  are  inhaled  and  some 
accumulate  in  the  stem  of  the  pipe,  so  that  an  old  pipe  gets 
"  strong."  The  pipe-smoker  tends  to  keep  more  or  less  under  the 
influence  of  tobacco  by  frequent,  short  smokes,  but  he  seldom 
inhales. 

The  cigar  is  less  rapidly  consumed  than  the  cigarette,  and  its 
area  of  ignition  is  greater,  so  that  the  tobacco  just  in  advance  of 
the  area  of  combustion  gets  hot;  consequently  there  is  some  vo- 
latilization of  the  raw  nicotine,  and  this  is  drawn  in  with  the  smoke. 
This  is  not  so  much  as  in  the  pipe;  but  the  fatter  the  cigar,  the 
greater  will  be  the  volatilization,  and  therefore  the  less  the  de- 
struction, of  the  nicotine.  Hence  the  smoke  of  a  thin  cigar,  and 
still  more  so  that  of  a  cigarette,  will  contain  less  of  the  raw, 
volatile  poisons  than  that  of  a  thick  cigar.  W.  E.  Lee  (1908) 
has  tested  the  relative  potencies  of  cigars  and  cigarettes  as  follows: 


41 0  PHARMACOLOGY  AND  THERAPEUTICS 

A  Manila  cigar  and  a  cigarette  of  Virginia  tobacco  of  nearly 
double  the  strength  of  the  Manila  tobacco  were  burned  so  that 
the  same  amount  of  tobacco  in  each  was  consumed  in  the  same 
time.  The  smoke  of  the  cigar  made  of  the  weaker  tobacco  was 
about  twice  as  toxic  as  that  from  the  cigarette. 

As  a  matter  of  fact,  the  cigarette  fiend  does  not  consume  any 
more  tobacco  than  the  cigar  or  pipe  fiend,  for  10  average  cigars 
represent  the  tobacco  of  50  or  60  cigarettes,  and,  as  we  have 
seen,  the  cigarette  is  the  least  harmful  form  of  tobacco.  Yet 
there  are  real  objections  to  the  cigarette,  viz.,  that  it  makes  smoking 
easy  for  the  young,  that  it  has  a  strong  tendency  to  induce  the 
habit  of  inhalation,  and  that,  being  small,  it  can  be  smoked  at 
odd  moments,  so  that  the  excessive  cigarette  smoker  tends  to  keep 
himself  under  some  influence  of  the  drug  all  day  long.  The  charges 
that  the  rice-paper  of  the  cigarette  produces  harmful  fumes, 
and  that  many  cigarettes  contain  opium,  have  been  repeatedly 
shown  to  be  without  foundation.  Indeed,  if  the  paper  is  impreg- 
nated with  potassium  nitrate  to  make  it  burn  evenly  and  with- 
out bursting  into  a  flame,  as  is  frequently  the  case,  it  has  a  ten- 
dency to  overcome  the  primary  rise  in  blood-pressure  which  is 
brought  on  by  the  nicotine. 

Those  who  lead  an  open-air  life  can  smoke  much  more  than 
those  who  remain  indoors.  Especially  bad  is  constant  smoking 
in  an  ill- ventilated  room,  for  more  or  less  of  the  smoke  is  rein- 
haled. 

Moderate  smoking  is  a  psychic  depressant,  favoring  ease  and 
comfort  and  "laissez-faire,"  rather  than  effort  and  work  and 
energy.  It  is  truly  narcotic.  In  so  far  as  it  is  a  habit  the  smoker 
may  feel  ill  at  ease  if  he  fails  to  get  his  usual  smoke;  yet  excessive 
smoking  may  be  given  up  at  once  and  absolutely  without  any 
rebellion  on  the  part  of  the  body.  It  is  easier  for  the  patient  if  he 
keeps  away  from  smokers  and  has  cheerful  company,  and  if  he 
chews  something  bitter  or  strongly  flavored,  such  as  gentian-root, 
lovage,  chewing-gum,  or  chocolate. 

Much  smoking  for  a  length  of  time  may  cause  various  dis- 
turbances, viz. : 

1.  Derangements  of  digestion  (especially  hyperchlorhydria) . 

2.  Headaches,  depressed  states  of  the  mind,  lack  of  energy, 
and  irritability  of  temper  (auto-intoxication). 

3.  Tobacco  amblyopia.  This  results  from  a  chronic  retrobul- 
bar neuritis  in  which  it  may  not  be  possible  to  detect  anything 
wrong  with  the  optic  disc,  but  vision  is  dulled  and  is  not  im- 
proved by  glasses.  Vision  is  often  better  in  a  dull  light  than  in 
a  bright  one  (de  Schweinitz) .  In  some  cases  the  optic  disc  may 
be  pale  and  somewhat  atrophied. 


PHYSOSTIGMA    (CALABAR   BEAN)  4II 

4.  Tobacco  heart — rapid,  irregular,  very  susceptible  to  nervous 
influence.  There  may  be  palpitation,  precordial  pain,  and  dysp- 
nea on  exertion.  Sudden  syncope  may  cause  death  in  high  alti- 
tudes, and  a  number  of  persons  with  tobacco  heart  have  died  in 
the  train  while  crossing  our  western  mountains.  Occasionally 
tobacco  causes  a  moderate  bradycardia. 

5.  Arteriosclerosis — atheroma  of  the  aorta  has  been  produced 
in  rabbits  by  nicotine,  by  infusion  of  tobacco,  and  by  inhalation 
of  tobacco  smoke.  It  is  not  at  all  improbable  that  tobacco  is  one 
cause  of  arteriosclerosis  in  man. 

6.  Deafness — either  from  the  production  of  catarrhal  con- 
ditions in  the  nasopharynx  and  Eustachian  tube,  or  from  an 
effect  on  the  nerve. 

Most  of  the  bad  effects  are  removed  by  the  stoppage  of  the 
drug  and  proper  hygiene,  i.  e.,  exercise,  fresh  air,  baths,  etc. 

The  local  irritation  of  the  nicotine  upon  the  tongue  has  been 
charged  with  the  production  of  epithelioma ;  that  of  the  smoke  on 
the  throat  with  the  production  of  catarrhal  conditions  or  hoarse- 
ness; that  of  the  swallowed  saliva  with  gastric  hyperesthesia  and 
gastritis.  Meylan,  of  Columbia  University,  in  summing  up  his 
studies  of  the  tobacco  habit  in  students,  says  that  it  is  generally 
conceded  that  the  use  of  tobacco  by  college  students  is  closely 
associated  with  idleness,  lack  of  ambition,  lack  of  application, 
and  low  scholarship.  Of  course,  these  are  not  due  entirely  to  the 
tobacco,  for  men  of  this  caliber  are  more  prone  to  carry  the  tobacco 
habit  to  excess  than  ambitious  workers. 

The  Peripheral  Nervous  Stimulants 

We  have  already  spoken  of  the  peripheral  sympathetic  stimu- 
lation of  cocaine  and  adrenaline,  and  the  primary  stimulation 
from  nicotine. 

PHYSOSTIGMA  (CALABAR  BEAN) 
The  ripe  seed  of  Physostigma  venenosum  (Fam.  Leguminosa) , 
yielding,  when  assayed,  not  less  than  0.15  per  cent,  of  alkaloid 
soluble  in  ether.  The  plant  is  a  woody  twiner  of  western  Africa, 
and  the  calabar  beans  were  used  by  the  native  medicine  men  for 
"trial  by  ordeal."  The  person  accused  of  a  crime  was  given  a 
paste  made  of  the  seeds;  if  he  recovered,  he  was  declared  innocent; 
if  he  died,  he  was  guilty.  It  is  said  that  if  enough  cattle  were  made 
over  to  the  priests  they  were  prone  to  mistake  harmless  seeds 
for  the  calabar  in  making  the  paste. 

Constituents. — The  alkaloid  physostigmine  or  eserine  is  an 
essential  ingredient.  There  are  also  minute  quantities  of  two  or 
three  other  alkaloids,  of  which  eseridine  or  iso physostigmine  has 


412  PHARMACOLOGY  AND  THERAPEUTICS 

the  action  of  physostigmine,  and  calabarine  that  of  strychnine. 
Physostigmine  in  solution  is  decomposed  by  light  or  heat,  and  a 
reddish  color  indicates  diminished  activity. 

Preparations  and  Doses. — 

Physostigma,  o.i    per  cent,  of  alkaloid;  dose,  1^2  grains 

(0.1  gm.). 
Extract,  2  per  cent,  of  alkaloid;  dose,  y&  grain  (0.008  gm.). 
Tincture,  10  per  cent.,  15  minims  (1  c.c). 

Physostigmine  salicylate,  soluble  in  72  of  water  and  13  of 
alcohol,  and  physostigmine  sulphate,  deliquescent  and  freely 
soluble  in  both  water  and  alcohol,  are  given  in  doses  of  -^ --^ 
grain  (0.001-0.002  gm.). 

Pharmacologic  Action. — Physostigmine  stimulates  the  se- 
cretory nerve-endings  of  glands  and  the  nerve-endings  of  striated 
and  smooth  muscle.  It  therefore  antagonizes  the  effects  of  atro- 
pine upon  secretion,  upon  the  action  of  smooth  muscle,  and  upon 
the  eye;  and  antagonizes  curare  in  its  effects  upon  striated  muscle. 
It  has  no  effect  on  sensory  nerve-endings. 

Secretion. — Physostigmine  is  not  employed  in  medicine  to 
increase  secretions,  for  by  arteriole  constriction  and  the  cutting- 
off  of  the  blood-supply  of  the  glands  the  amount  of  the  secretion 
is  limited. 

Muscle. — Its  effect  upon  the  action  of  smooth  muscle  is 
strongest  in  the  alimentary  tract,  so  that  it  may  be  employed, 
either  by  mouth  or  hypodermatically,  as  a  cathartic.  It  also 
tends  to  cause  contraction  of  the  bladder,  ureters,  bronchi,  and 
spleen,  and  perhaps  also  of  the  uterus. 

Its  effect  upon  the  action  of  striated  muscle  is  shown  in  the 
isolated  gastrocnemius  by  increased  irritability  and  increased 
power  to  lift  a  load.  Irregular  stimulation  in  man  is  also  indicated 
.by  peculiar  fascicular  spasms  or  twitchings  of  the  muscle,  as  in  the 
temporal  or  orbital  muscles  when  the  drug  is  used  in  the  eye,  or 
in  the  muscles  of  the  limbs  in  poisoning.  It  is  directly  antidotal 
to  the  peripheral  action  of  curare,  and  presumably  acts  upon  the 
same  structures. 

The  Pupil. — If  a  drop  of  1 :  200  aqueous  solution  of  eserine  is 
placed  in  the  eye,  contraction  of  the  pupil  begins  in  one  or  two 
minutes  and  reaches  its  maximum  in  one-half  to  one  hour.  The 
marked  contraction  lasts  from  twelve  to  thirty-six  hours,  and  the 
normal  size  of  the  pupil  is  regained  in  from  two  to  four  days.  The 
contraction  is  due  to  stimulation  of  the  ends  of  the  third  nerves, 
physostigmine  not  contracting  the  pupil  after  degeneration  of  the 
nerve  (Anderson). 

Accommodation. — Through  similar  action  on  the  ends  of  the 


PHYSOSTIGMA    (CALABAR    BEAN)  413 

third  nerve,  the  ciliary  muscle  contracts  like  the  circular  muscle 
of  the  iris,  and  allows  the  lens  to  bulge  forward.  This  causes  the 
sight  to  be  fixed  in  accommodation  for  near  objects,  while  objects 
more  than  a  few  feet  away  are  out  of  focus.  There  is  sometimes 
supra-orbital  or  eyeball  pain  from  continued  overaction  of  this 
muscle.  The  accommodation  returns  to  normal  somewhat  more 
quickly  than  the  pupil. 

Intra-ocular  tension  is  much  lowered,  without  any  essential  pre- 
liminary rise  in  tension.  This  lowering  is  usually  considered  due 
to  the  increased  escape  of  fluid  through  the  spaces  of  Fontana, 
which  are  promptly  opened  up  by  the  contraction  of  the  pupil; 
but  Gronholm  attributes  much  of  the  fall  of  tension  to  contraction 
of  the  vessels  and  consequently  diminished  secretion. 

The  use  of  the  drug  in  the  eye  may  be  followed  by  disagree- 
able or  painful  twitchings  of  the  eyelid,  or  fascicular  spasms  of 
the  adjoining  face  or  temporal  muscles.  Physostigmine  is  much 
more  powerful  than  pilocarpine  as  an  antagonist  of  atropine. 

Circulation. — The  effect  upon  the  heart  and  arteries  is  but 
poorly  understood.  Small  doses  slow  the  heart,  and  as  this  effect 
follows  large  doses  of  atropine,  it  cannot  be  due  to  vagus  center 
stimulation.  Some  authors  believe  there  is  a  stimulation  of  the 
vagus  nerve-endings.  In  the  frog  there  are  direct  muscle  stimu- 
lation and  increased  irritability,  but  in  mammals  strengthening 
is  not  usually  seen.  The  arterioles  are  contracted  from  peripheral 
stimulation,  probably  chiefly  of  the  ends  of  the  vasoconstrictor 
nerves,  for  Dixon  says  there  is  no  contraction  after  apocodeine. 
Arterial  pressure  is  raised.  There  is  apparently  no  effect  upon  the 
vasoconstrictor  center.  In  poisoning,  both  heart  muscle  and  vaso- 
constrictor mechanism  are  depressed  so  that  the  arterial  pressure 
falls. 

Respiration  is  at  first  quickened  and  deepened,  from  stimula- 
tion of  the  center  and  probably  of  the  afferent  vagus  endings  in 
the  bronchi.  In  poisoning  there  is  depression  of  the  center,  and 
there  may  be  asthmatic  breathing  from  contraction  of  the  bron- 
chial muscles.     Death  is  due  to  failure  of  the  respiratory  center. 

Nervous  System. — The  cerebrum  is  little  affected,  conscious- 
ness in  fatal  poisoning  remaining  until  near  the  end.  The  vital 
medullary  centers  are  at  first  stimulated,  then  depressed.  The 
reflexes  are  depressed,  and  in  poisoning  there  may  be  an  ascend- 
ing paralysis,  beginning  in  the  legs.  The  effect  on  peripheral 
nerves  has  been  spoken  of ;  there  is  no  effect  on  sensory  nerves. 

Excretion  is  rapid  by  the  urine.  A  slight  amount  appears  in 
the  saliva  and  bile. 

Toxicology. — Noteworthy  are  the  marked  muscular  weakness 
without  loss  of  consciousness.     The  pupils  are  markedly  con- 


414  PHARMACOLOGY  AND  THERAPEUTICS 

traded,  the  skin  covered  with  sweat,  there  are  vomiting,  diarrhea, 
and  cramps  in  the  abdomen.  The  loss  of  muscular  power  begins  in 
the  legs  and  ascends,  and  is  accompanied  by  twitching  or  tremor. 
The  heart  is  at  first  slow  and  the  arterial  pressure  good ;  later  the 
heart  becomes  weak  and  slow,  and  the  blood-pressure  is  lowered. 
The  respiration  is  at  first  rapid  and  deep,  then  becomes  shallow 
and  labored  or  perhaps  asthmatic.  Death  occurs  from  paralysis 
of  respiration.  The  antidote  is  atropine  for  the  asthma,  the 
diarrhea,  and  the  intestinal  cramps;  if  necessary,  the  patient 
must  be  treated  for  collapse,  bearing  in  mind  that  the  heart  itself 
is  very  weak.  Joseph  and  Meltzer  recommend  magnesium  sul- 
phate as  partly  antidotal.  It  can  be  used  subcutaneously  or  in 
the  spinal  canal,  the  dose  being  i  dram  (4  c.c.)  of  a  25  per  cent, 
solution. 

Therapeutics. — The  extract  in  pills,  and  the  salts  of  physos tig- 
mine  hypodermatically,  are  used  as  cathartics.  Since  not  many 
drugs  will  act  as  cathartics  when  administered  hypodermatically, 
a  knowledge  of  this  power  of  physostigmine  may  be  of  value  in 
some  severe  illnesses  or  postoperative  conditions. 

The  physostigmine  salts,  usually  in  a  solution  of  1  :  200, 
are  much  employed  in  the  eye  to  lessen  the  high  intra-ocular 
tension  of  glaucoma,  and,  after  drugs  of  the  atropine  class, 
to  hasten  the  return  of  the  pupil  and  accommodation  to  normal. 
They  are  preferred  to  pilocarpine  because  their  action  lasts 
longer  and  is  more  complete,  and  there  is  no  noteworthy  pre- 
liminary rise  of  intra-ocular  tension. 

A  disadvantage  is  the  nervous  spasm  of  the  eyelid  and  tem- 
poral muscles,  which  may  occur  frequently  during  several  hours. 

PILOCARPUS  (JABORANDI) 

The  leaflets  of  Pilocarpus  jaborandi  or  of  Pilocarpus  micro- 
phyllus  (Fam.  Rutacece),  yielding,  when  assayed,  not  less  than 
0.5  per  cent,  of  alkaloids.    It  is  a  Brazilian  shrub. 

Constituents. — The  alkaloid  pilocarpine,  also  isopilocarpine 
and  pilocarpidine,  with  similar  action,  and  jaborine,  which  acts 
like  atropine  but  occurs  in  too  minute  quantity  to  have  any 
effect. 

Preparations  and  Doses. — 

Pilocarpus,  0.5  per  cent,  alkaloid;  dose,  30  grains  (2  gm.). 

Fluidextract,  0.4  per  cent,  alkaloid;  dose,  30  minims  (2  c.c). 

Pilocarpine  chloride  and  pilocarpine  nitrate;  dose,  %  grain 

(0.01  gm.),  the  former  being  readily  soluble  in  alcohol 

and    water,    the  latter  in  water    but   less  readily  in 

alcohol  (1  :6o). 


PILOCARPUS    (jABORANDl)  415 

Pharmacologic  Action. — Pilocarpine  is  directly  antagonistic 
to  atropine  in  its  effects  upon  the  ends  of  the  secretory  nerves, 
the  ends  of  the  nerves  governing  smooth  muscle,  the  ends  of  the 
vagus  nerves,  and  the  ends  of  the  third  nerve  in  the  internal  eye. 
In  strong  solution  it  slightly  stimulates  the  gland  and  muscle 
cells.  It  does  not  affect  the  sensory  nerve-endings  or  the  striated 
muscle  or  their  motor  end-plates.  As  with  atropine,  pilocarpine 
acts  after  nerve  degeneration,  and  is  presumed  to  affect  a  material 
which  serves  as  receptor  of  nerve  impulses.  For  practical  pur- 
poses we  can  speak  of  its  acting  on  the  nerve-endings. 

Secretion. — The  secretion  chiefly  affected  is  that  of  the  sweat, 
pilocarpine  being  a  very  powerful  diaphoretic.  According  to 
Edmunds  and  Cushny,  a  man  may  lose  from  4  to  9  pounds  in 
weight  after  a  single  dose;  other  observers  also  have  estimated 
that  the  sweat  may  amount  to  a  gallon,  the  solid  as  well  as  the 
liquid  portion  being  increased  in  total  quantity.  The  sweating 
takes  place  after  the  nerves  to  the  glands  have  been  cut  peripheral 
to  the  ganglia,  so  the  drug  must  act  on  the  nerve-ending  or  the 
cell.  The  sweating  is  completely  checked  by  atropine.  As  it  takes 
much  more  atropine  than  normally,  it  is  believed  that  pilocarpine 
stimulates  the  structures  that  atropine  depresses,  viz.,  the  re- 
ceptor substance  between  nerve-ending  and  muscle.  There  is 
some  evidence  that  pilocarpine  also  acts  slightly  on  the  ganglia. 
The  sweat  is  acid  or  neutral  from  the  fatty  acids  of  the  sebaceous 
secretion,  the  sebaceous  glands  sharing  in  the  stimulation. 

The  saliva  and  bronchial  mucus  are  also  considerably  in- 
creased, and  to  some  extent  also  the  ear-wax  and  tears,  the  gastric, 
pancreatic,  and  intestinal  juices,  and  all  the  mucous  secretions. 
In  very  weak  conditions  the  bronchial  mucus  may  accumulate 
to  such  a  degree  as  to  interfere  with  the  breathing  and  favor  the 
development  of  edema  of  the  lungs.  All  these  secretory  effects  are 
prevented  by  atropine.  The  quantity  of  milk,  of  bile,  and  of 
urine  are  not  directly  affected.  It  is  stated  that  the  sugar  in  the 
blood  and  the  sugar  in  the  milk  are  increased  in  amount. 

It  is  an  interesting  fact  that,  both  from  the  local  application 
of  the  drug  to  the  scalp  and  its  internal  administration,  the  hair, 
in  some  cases,  increases  in  abundance.  This  result  is  due,  prob- 
ably, to  the  increase  of  the  scalp  secretions.  The  new  hair  may 
be  of  a  lighter  shade  and  give  a  patchy  appearance.  To  test 
this  Pringle  (1908)  injected  ]/2  grain  (0.03  gm.)  of  pilocarpine 
nitrate  into  the  scalp,  and  got  a  growth  of  hair  as  the  result. 

Smooth  muscle  shows  its  increased  activity  only  after  poisonous 
doses,  the  chief  manifestations  being  increased  peristalsis  in  the 
alimentary  tract  and  contraction  of  the  bronchi,  bladder,  and 
pupil.    The  effects  are  due  to  stimulation  of  the  nerve-endings, 


41 6  PHARMACOLOGY  AND  THERAPEUTICS 

and  are  prevented  by  atropine.     The  arterial  muscles  are  not 
affected,  and  probably  not  the  uterus. 

The  Eye. — A  0.5  to  1  per  cent,  solution,  dropped  in  the  eye, 
has  the  following  effects: 

(a)  Pupil. — There  is  stimulation  of  the  third  nerve-endings, 
with  contraction  of  the  pupil,  the  maximum  contraction  being 
reached  in  one-half  to  one  hour,  and  lasting  only  three  or  four 
hours. 

(b)  Accommodation. — The  ends  of  the  third  nerve  in  the 
ciliary  muscle  are  stimulated;  hence  this  circular  muscle  contracts 
and  causes  bulging  of  the  lens  and  fixation  of  the  eye  in  accom- 
modation for  short  distances.  There  may  be  a  dull  pain  from  the 
continued  muscular  contraction. 

(c)  Intra-ocular  Tension. — After  a  preliminary  rise,  lasting 
sometimes  as  much  as  half  an  hour,  and  probably  brought  on  by 
increased  secretion,  the  tension  falls.  The  fall  is  more  or  less 
coincident  with  the  pupil  contraction,  and  results  from  the  in- 
creased escape  of  fluid  which  follows  the  opening  of  the  lymphatic 
outlets  (spaces  of  Fontana)  when  the  pupil  contracts. 

Circulation. — From  large  doses  the  heart  is  usually  slowed 
and  slightly  weakened,  this  action  being  due  solely  to  stimulation 
of  the  vagus  endings,  and  being  preventable  by  atropine.  From 
very  poisonous  doses,  the  vagus  ends  may  become  paralyzed,  but 
the  heart  muscle  itself  is  directly  depressed,  so  that  the  beat 
continues  slow.  Sometimes  the  heart  beats  faster  at  first  from 
vagus  center  depression.  After  toxic  doses  the  arterioles  are 
dilated  by  depression  of  the  vasoconstrictor  center,  and  blood- 
pressure  falls. 

Pilocarpine  is,  therefore,  a  cardiac  depressant,  both  vagus  and 
direct,  and  in  excessive  doses  an  arterial  dilator.  Its  margin  of 
safety  is  small,  and  its  administration  in  conditions  of  cardiac 
weakness  has  been  followed  in  some  cases  by  collapse  and 
death.  The  author  has  seen  two  cardionephritic  cases  die  from 
the  combined  effects  of  pilocarpine  chloride,  TV  grain  (0.006 
gm.),  and  a  hot-pack. 

Respiratory  Tract. — Owing  to  the  increased  bronchial  secretion 
and  contraction  of  the  bronchial  muscles  from  stimulation  of  the 
ends  of  the  bronchomotor  nerves,  the  breathing  in  poisoning  may 
be  labored  or  asthmatic;  at  the  same  time  there  is  depression  of 
the  respiratory  center.  These  factors,  joined  to  weakness  of  the 
circulation,  tend  to  promote  edema  of  the  lungs,  asphyxia,  collapse, 
and  death. 

Nervous  System. — The  mind  remains  clear  in  pilocarpine  poison- 
ing, but  there  is  depression  of  the  medullary  centers  and  of  the 
spinal  reflexes,  and  there  may  be  muscular  weakness  or  paralysis. 


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MUSCARINE    AND   MUSHROOM  POISONING  417 

Elimination. — In  the  sweat,  urine,  and  saliva. 

Toxicology. — As  in  physostigmine  poisoning,  there  is  prostra- 
tion without  loss  of  consciousness.  There  is  at  first  excessive  vagus 
action  and  depression  of  the  vasoconstrictor  center,  with  slowed 
or  intermittent  heart-beat  (vagus  standstill  or  vagus  heart-block) 
and  low  blood-pressure.  Later  there  is  slow,  feeble  heart-beat  and 
collapse. 

The  pupil  is  strongly  contracted,  the  skin  flushed  and  pro- 
fusely sweating,  and  the  saliva  abundant.  There  may  be  nausea, 
vomiting,  diarrhea,  and  abdominal  cramps.  The  respiration  may 
be  labored,  asthmatic,  with  the  physical  signs  of  increased  bron- 
chial mucus  or  edema  over  both  lungs;  there  may  be  muscular 
relaxation,  beginning  in  the  lower  limbs  and  ascending.  Con- 
sciousness, though  dulled,  persists  until  near  the  end.  Death 
takes  place  in  collapse,  with  edema  of  the  lungs. 

The  treatment  is  atropine  hypodermatically,  and  the  general 
treatment  for  collapse,  especially  artificial  respiration.  The  atro- 
pine serves  to  overcome  the  asthmatic  breathing,  to  lessen  bron- 
chial secretion,  to  diminish  cramps  in  the  abdomen,  and  to  check 
excessive  vagus  action. 

Therapeutics. — The  fluidextract  is  added  to  hair-washes,  the 
pilocarpine  salts  being,  as  a  rule,  considered  too  expensive. 

In  the  eye,  a  i :  200  solution  of  pilocarpine  chloride  is  used  in 
glaucoma,  and  to  hasten  contraction  of  the  pupil  after  mydriatics; 
but  physostigmine  is  usually  preferred. 

Internally,  it  has  been  employed  in  chronic  congestive  con- 
ditions of  the  middle  ear,  in  labyrinthine  affections,  and  in  con- 
gestive conditions  of  the  eye.  Its  good  effects  seem  to  depend 
largely  on  the  resulting  diaphoresis.  It  has  also  been  used  as  an 
expectorant  in  the  dry  stage  of  bronchitis,  but  it  makes  profuse 
sweating  and  salivation. 

Its  chief  use  is  as  a  diaphoretic  in  nephritis  with  uremia  and  in 
dropsy.  Tyson  recommends  10  minims  of  the  fluidextract  three 
times  a  day,  or  a  daily  dose  of  %  grain  of  pilocarpine  chloride. 
Because  of  its  tendency  to  depress  the  heart  or  produce  edema  of 
the  lungs,  its  effects  must  be  watched;  and  it  should  not  be 
employed  if  the  heart  is  weak. 

MUSCARINE  AND  MUSHROOM  POISONING 
Muscarine  is  an  alkaloid  contained  in  the  mushroom  known 
as  the  fly  agaric,  Amanita  muscaria,  and  in  some  other  agarics. 
Its  actions  are  very  similar  to  those  of  pilocarpine,  but  stronger, 
hence  in  poisoning  by  the  fly  agaric  we  get  the  same  symptoms 
as  from  pilocarpine  poisoning.  The  symptoms  come  on  very 
quickly.  Muscarine  is  not  destroyed  by  cooking.  Atropine  is  the 
27 


41 8  PHARMACOLOGY  AND   THERAPEUTICS 

best  antidote,  and  the  stomach  should  be  washed  out  or  an  emetic 
given,  and  general  treatment  for  collapse  instituted.  Muscarine 
is  not  used  in  medicine,  as  it  is  more  dangerous  and  more  irri- 
tant to  the  stomach  than  pilocarpine. 

Most  of  the  cases  of  mushroom  poisoning,  however,  are  due  to 
the  death's-head  fungus,  Amanita  phalloides,  and  related  species, 
which  contain  little  if  any  muscarine,  but  depend  for  their  poison- 
ous action  upon  a  substance  which  has  the  nature  of  a  toxin.  It 
is  characteristic  of  a  toxin  that  the  symptoms  are  manifested  only 
after  a  latent  period,  and  that  immunity  may  be  established 
toward  it  in  susceptible  animals  by  the  repeated  administration  of 
non-lethal  doses.  This  toxin  is  destroyed  by  prolonged  cooking. 
Ford  has  prepared  a  serum  which  is  antitoxic  and  antihemolytic 
to  the  amanita  toxin. 

The  symptoms  come  on  after  a  latent  period  of  ten  or  twelve 
hours.  They  are  great  thirst,  vomiting,  diarrhea,  cramps  in  the 
stomach  and  limbs,  headache,  cerebral  stimulation  up  to  a  state 
of  delirium,  and  sometimes  suppression  of  the  urine.  After 
twelve  to  twenty-four  hours  jaundice  may  appear  from  extensive 
hemolysis.  Collapse  soon  follows  from  a  toxic  action  upon  the 
heart  muscle;  or  the  sickness  continues  for  several  days,  resem- 
bling an  infectious  disease. 

The  treatment  is  to  wash  out  the  stomach  and  the  colon,  apply 
an  ice-bag  to  the  head,  and  give  morphine  by  hypodermatic.  If 
collapse  ensues,  treat  for  collapse.  Atropine  is  of  no  value,  and 
Ford 's  serum  would  hardly  be  obtainable  when  wanted. 

Ford  has  attempted  to  divide  the  poisonous  fungi  into  three 
groups,  viz.: 

i.  Those  containing  poisons  acting  on  the  nervous  system,  as 
Amanita  muscaria. 

2.  Those  producing  degenerative  changes  in  the  internal 
organs,  as  Amanita  phalloides,  Amanita  verna,  etc. 

3.  Those  causing  gastro-intestinal  irritation  with  violent  man- 
ifestations, as  Lactarius  torminosus,  Clitocybe  illudens,  Entoloma 
sinuatum,  etc. 

The  Amanita  muscaria,  or  fly  agaric,  is  highly  colored  with 
yellow  and  orange  and  reddish  tints.  Its  stem  is  longer  than  the 
diameter  of  the  cap,  bulges  at  the  base,  and  bears  a  collar  or  ring 
of  tissue.  The  cap  is  deep  yellow  or  orange  or  greenish-yellow,' and 
bears  numerous  scattered  white  or  yellow  scales.  The  gills  on  the 
under  surface  of  the  cap  are  white.  It  has  a  fungous  odor  and 
grows  in  open  woods  or  along  roadsides  near  trees. 

The  Amanita  phalloides  (death's-head  fungus,  deadly  agaric) 
is  white  throughout  or  slightly  brownish.  The  stem  often  arises 
from  a  cup,— the  so-called  "death's-head"  or  " poison-cup," — 


Fig   <o.— Amanita  phalloides,  white  form,  showing  cap  stem  ring  and  cup.     (From 
^l-inCnn's  "Mushrooms."  Henrv  Holt  &  Co.,  Publishers.) 


Fjg    -l— Agaricus  campestris.     View  of  under  side,  showing  stem,  ring,  gills,  and 
marein  of  can.     (From  Atkinson's  "Mushrooms,"  Henry  Holt  &  Co.,  Publishers.) 


DIAPHORETICS  419 

bulges  at  the  base,  is  longer  than  the  diameter  of  the  cap,  and  near 
the  cap  is  surrounded  by  a  collar  of  tissue  (the  annulus  or  ring) ; 
it  tends  to  turn  dark  where  bruised.  The  cap  is  white,  or  slightly 
yellowish  or  greenish-white,  or  brownish,  and  its  under  surface 
bears  the  persistently  white  gills.  It  has  a  typical  fungous  odor, 
and  grows  in  open  woods  or  along  the  borders  of  woods. 

The  common  edible  mushroom  or  field  mushroom  is  Agaricus 
campestris.  It  is  stubby  in  growth.  Its  stem  is  shorter  than  the 
diameter  of  the  cap,  is  cylindric,  and  instead  of  being  bulbous  is 
narrowed  at  the  base;  it  does  not  emerge  from  a  cup,  and,  except 
for  the  first  hour  or  two  after  maturity,  is  usually  without  an 
annulus  or  ring.  Its  cap  is  white  to  brownish,  and  bears  on  its 
under  surface  the  notably  pink  gills,  which  become  purplish-brown 
when  a  few  hours  old,  and  turn  blackish-brown  on  keeping.  It  has 
an  earthy  smell,  like  potatoes,  rather  than  a  fungous  smell,  and 
grows  in  fields,  lawns,  or  by  roadsides. 

DIAPHORETICS 

A  diaphoretic  is  a  remedy  which  tends  to  induce  profuse 
sweating.    Profuse  sweating  is  diaphoresis. 

The  measures  employed  to  produce  diaphoresis  are  either  drugs 
or  methods  of  raising  and  keeping  raised  the  body-heat.  We  do 
not  here  consider  terror,  nausea,  great  weakness,  and  other  causes 
of  profuse  sweating,  as  these  are  not  therapeutic  agents. 

1.  The  drugs  in  common  use  are:  pilocarpine,  whisky,  Dover's 
powder  (pulvis  ipecacuanha?  et  opii),  the  spirit  of  Mindererus 
(liquor  ammonii  acetatis),  and  the  sweet  spirit  of  niter  (spiritus 
astheris  nitrosi),  all  of  which  we  have  already  studied.  Many 
other  drugs  tend  to  increase  the  sweat,  but  are  not  employed  for 
that  express  purpose  in  therapeutics. 

2.  Methods  of  raising  body-heat  and  keeping  it  raised  for 
diaphoretic  purposes : 

(a)  Increasing  the  production  of  heat,  as  by  exercise. 

(b)  Prevention  of  heat-loss,  as  with  blankets  or  extra  bed- 
clothes, or  heavy  woolen  sweaters,  as  during  exercise. 

(c)  The  use  of  artificial  heat,  either  internally  or  externally — 
internally,  by  hot  drinks,  and  externally,  by  hot  air,  hot  baths, 
vapor  baths,  electric  baths,  etc.  A  Turkish  bath  involves  remain- 
ing in  dry  hot  air  at  1400  to  1600  F.  for  a  length  of  time.  A  Rus- 
sian bath  is  similar,  but  the  air  is  surcharged  with  aqueous  vapor. 

Water  taken  internally  is  both  diaphoretic  and  diuretic.  It 
is  not  cathartic,  for  the  intestines  can  absorb  such  enormous 
quantities  that,  in  normal  conditions  at  least,  the  excess  does  not 
pass  out  by  the  rectum,  but  is  excreted  by  the  kidneys  and  skin 


420  PHARMACOLOGY  AND  THERAPEUTICS 

(Starling).  Cold  water  alone  is  essentially  diuretic  rather  than 
diaphoretic,  the  sweat  being  increased  to  only  a  slight  degree. 
But  large  drinks  of  hot  water,  as  in  the  form  of  hot  lemonade  or 
chamomile  tea,  or  large  drinks  of  cold  water  plus  measures  which 
increase  body-heat  and  set  in  action  the  heat-regulating  mechan- 
ism (as  hot  air,  hot  baths,  exercise,  etc.),  result  in  a  copious  out- 
pouring of  sweat. 

It  is  our  custom  in  therapeutics  to  combine  the  measures.  For 
example : 

i.  In  exercising  to  remove  fat  a  sweater  or  two  is  worn  to 
prevent  heat-loss  by  evaporation  of  the  sweat. 

2.  To  check  a  cold,  a  liberal  draft  of  hot  lemonade  or  water  at 
bed-time,  with  or  without  whisky,  is  assisted  by  extra  bed-cloth- 
ing, and  sometimes  a  preliminary  hot  bath. 

3.  In  nephritis  and  dropsical  conditions  the  hot-pack  or  hot- 
air  bath  is  employed,  with  sometimes,  in  addition,  a  hypoder- 
matic of  pilocarpine  chloride,  yu  grani  (0.006  gm.). 

The  hot-pack  gives  a  combination  of  increased  external  heat 
with  prevention  of  heat-loss.  In  giving  a  hot-pack  the  patient, 
all  except  the  head,  is  wrapped  in  a  blanket  or  sheet  (the  arms 
being  separated  from  the  body  by  a  layer  of  material) ,  then  suc- 
cessively in  two  blankets  which  have  been  wrung  out  of  very  hot 
water,  then  perhaps  in  a  rubber  sheet,  with  the  bed-clothes  over 
all.  He  is  kept  thus  for  from  fifteen  to  thirty  minutes.  If  the  hot- 
pack  is  not  for  dropsy,  a  copious  drink  of  water  or  lemonade  may 
be  administered;  if  it  is  for  dropsy,  liquid  must  not  be  given.  To 
prevent  headache,  an  ice-bag  or  wet  cold  cloth  should  be  applied 
to  the  head. 

The  electric  bath,  the  hot-air  bath,  and  the  vapor  bath  are 
sometimes  used  for  the  same  purposes.  The  electric  bath  is  given 
in  a  cabinet  in  which  the  patient  sits  (head  out) ,  surrounded  by 
electric  lights.  In  the  hot-air  and  vapor  baths  the  patient, 
wrapped  in  a  sheet,  sits  in  a  cabinet  or  tent  with  the  head  out;  or 
if  in  bed,  may  have  a  sheet  hung  over  him  in  the  form  of  a  tent. 
A  heater  in  the  tent  or  cabinet,  or  hot  air  conducted  into  the  tent 
by  a  pipe,  makes  a  hot-air  bath ;  the  steam  from  a  kettle  makes  a 
vapor  bath.  Cold  applications  to  the  head  during  the  bath  tend 
to  prevent  headache. 

By  any  of  these  methods  copious  sweating  is  produced,  even 
to  the  amount  of  several  quarts ;  and  if  the  skin  is  not  exposed  to 
cold,  the  production  of  sweat  may  continue  above  normal  for  as 
much  as  twenty-four  hours.  If,  however,  sweating  does  not 
result,  there  may  be  headache  and  feelings  of  faintness,  and  even 
collapse,  as  sometimes  occurs  in  the  Turkish  bath.  Even  when 
there  is  profuse  sweating,  collapse  sometimes  takes  place  in  a  hot- 


DIAPHORETICS  4  2 1 

pack,  and  especially  is  this  likely  after  pilocarpine;  so  in  serious 
heart  conditions,  or  if  there  is  a  tendency  to  edema  of  the  lungs, 
diaphoretic  measures  must  be  used  with  caution.  Nevertheless, 
as  a  rule,  profuse  sweating  is  not  so  exhausting  as  repeated  ca- 
tharsis. 

During  or  immediately  following  a  copious  sweat,  exposure  to 
cold  may  result  in  chilling  of  the  surface,  with  contraction  of  the 
skin  vessels  and  internal  congestion,  i.e.,  a  cold.  Therefore,  be- 
fore going  out  after  a  heavy  sweat  one  should  have  a  cold  sponge 
or  shower  with  a  good  rubbing  down  of  the  skin  and  a  short 
period  of  rest. 

The  Rationale  of  Sweating. — Normally,  the  loss  of  heat 
through  the  skin  is  due  to  radiation  and  convection  from  the  sur- 
face of  the  body,  and  to  the  cooling  effect  of  the  evaporation  of 
sweat.  It  is  largely  by  sweating  that  the  heat-loss  of  the  body- 
is  normally  increased.  Ordinarily,  the  evaporation  of  the  sweat 
keeps  pace  with  its  production,  so  that  the  sweat  does  not  gather 
into  perceptible  moisture.  But  when  the  sweat  cannot  evaporate 
as  rapidly  as  it  is  produced,  as  during  exercise,  or  in  a  humid 
atmosphere,  or  for  other  reasons,  the  perspiration  collects  and 
becomes  visible.  Perspiration  that  is  visible  indicates  that  the 
heat-regulating  mechanism  has  overdone  the  production  of  sweat, 
and  that  more  is  produced  than  under  the  existing  circumstances 
can  be  utilized  for  cooling  purposes. 

When  radiation  and  convection  from  the  surface  of  the  body 
are  prevented  by  an  external  temperature  above  that  of  the  body, 
as  in  these  hot-bath  methods,  the  body  temperature  rises.  The 
result  of  the  rise  is  stimulation  of  the  heat-regulating  mechanism, 
and  this  sets  to  work  the  sweat-glands,  for  this  is  its  usual  way  to 
bring  about  cooling.  But  as  this  mechanism  does  not  discriminate, 
the  sweat  continues  to  form  even  though  the  conditions  are  such 
that  the  sweating  cannot  serve  its  usual  purpose  in  cooling  the 
body.  Just  as  long,  therefore,  as  there  is  a  heightened  body- 
temperature  the  sweating  continues,  in  a  futile  attempt  of  the 
heat-regulating  mechanism  to  bring  the  body-temperature  to 
normal  in  the  usual  way. 

In  the  methods  for  inducing  diaphoresis  it  is  this  tendency  of 
the  sweating  mechanism  to  respond  to  raised  body-heat,  of  which 
advantage  is  taken.  For  so  long  as  the  sweat  is  prevented  from 
accomphshing  its  object  of  cooling  the  body,  the  sweating  will 
continue  indefinitely.  Hence  the  use  of  exercise,  hot  drinks,  and 
hot-air  and  hot-water  baths  to  increase  the  body-heat;  and  of 
blankets,  sweaters,  etc.,  to  lessen  the  heat  radiation  and  to  absorb 
the  sweat  and  prevent  its  evaporation  at  the  surface  of  the  body. 


42  2  PHARMACOLOGY  AND  THERAPEUTICS 

Fat. — In  a  sense  there  is  a  protective  garment  about  a  fat  per- 
son, the  thick,  poorly  conducting  layer  of  fat  interfering  with  heat- 
loss;  so  that  if  the  internal  temperature  is  raised,  an  excessive 
amount  of  sweat  is  poured  out  in  the  vain  effort  of  the  body  to 
cool  itself.  On  a  hot,  humid  day  a  fat  man  sweats  more  profusely, 
yet  suffers  more  from  the  heat  than  the  thin  man.  If  a  fat  person 
ingests  no  water  while  carrying  out  diaphoretic  measures,  the 
body  tends  to  form  water  from  the  fat,  and  so  lessen  its  adipose 
deposit.  Von  Noorden  says  that  ioo  grams  of  fat  yield  107  grams 
of  water,  and  he  states  that  restriction  of  the  water  intake  pro- 
duces a  loss  of  fat.  But  he  quotes  Heilner  and  also  Henneberg  as 
authorities  for  the  statements  that  in  experimental  animals  abun- 
dant water-drinking  increases  fat  catabolism,  and  in  stock-raising 
renders  it  very  difficult  to  fatten  animals.  Yet  by  vigorous  daily 
exercise,  wearing  heavy  sweaters,  limitation  of  the  fluids,  and 
regulation  of  the  food  ingested,  a  fat  man  may  lose  40  or  50 
pounds  of  his  weight  in  a  few  months  and  yet  feel  in  splendid 
condition. 

The  Character  of  the  Sweat  in  Diaphoresis. — The  normal  se- 
cretion of  the  sweat-glands  is  of  low  specific  gravity  and  of  faintly 
alkaline  reaction,  and  there  are  various  salts  present.  The  slight 
acidity  sometimes  noted  is  due  to  admixture  with  the  sebaceous 
secretion.  With  copious  sweating  by  raising  body-heat,  or  by 
drugs  which  do  not  act  specifically  on  the  sebaceous  glands,  we 
get  a  slightly  alkaline  secretion.  With  pilocarpine,  on  the  con- 
trary, which  specifically  stimulates  both  the  sweat  and  the  se- 
baceous glands,  the  secretion  tends  to  be  acid,  or  at  least  not  alka- 
line, owing  to  the  presence  of  the  fatty  acids  of  the  sebaceous 
material. 

The  Relation  of  Diaphoresis  to  Nitrogenous  Excretion. — The 
ordinary  insensible  perspiration  does  not  contain  any  appreciable 
nitrogenous  matter  (Lusk) .  The  average  of  many  tests  by  different 
experimenters  gives  0.068  gm.  nitrogen  per  day  in  skin  elimination. 

Benedict  (1906)  got  0.071  gm.  nitrogen  per  day  in  the  whole 
cutaneous  secretions,  both  sebaceous  and  sweat,  of  a  resting  man. 
"But  when  the  sweat  was  increased,  as  in  a  man  at  moderate  work, 
the  nitrogen  from  the  skin  rose  to  0.13  gm.  per  hour,  and  in  a  man 
at  hard  work  to  0.22  gm.  per  hour.  The  nitrogen  of  these  larger 
quantities  represented  urea,  uric  acid,  creatinin,  and  other  con- 
stituents of  urine."  Therefore,  copious  sweating  from  hard  work, 
which  Atwater  and  Benedict  found  might  be  eight  times  the 
normal  sweating,  represented  the  loss  of  1  gm.  of  nitrogenous 
excreta  in  five  hours.  This  shows  that  the  sweat-glands  of  normal 
persons  can,  to  some  degree,  be  made  to  take  on  a  function  of  the 
kidneys.    But  in  this  work  there  was  greatly  increased  muscular 


DIAPHORETICS  423 

activity,  i.  e.,  increased  metabolism,  and  consequently  the  results 
are  not  indicative  of  the  real  excretory  value  of  diaphoresis  in 
sick  people. 

Some  of  the  striking  experiments  on  diaphoresis  are  worth 
noting : 

Hoelscher,  in  22  experiments  with  hot-air  baths,  obtained 
6719  c.c.  of  sweat,  containing  a  total  nitrogen  of  0.48  gm.  per 
1000  c.c.  Eijkmann  studied  three  medical  students  at  light  occu- 
pation in  the  climate  of  Java.  In  three  hours  he  obtained  0.2  2  2  gm. 
nitrogen;  in  twenty-four  hours,  0.761  and  1.362  gm.  nitrogen. 

Benedict  experimented  with  a  man  twenty- four  years  old,  75 
kilos  in  weight,  at  rest  in  the  respiration  chamber  during  four  days 
of  fasting  and  then  three  days  with  food.  The  average  daily 
nitrogen  excreted  by  the  skin  was  0.103  gm.  When  such  a  man 
did  eight  hours'  work  on  a  stationary  bicycle  in  the  respiratory 
calorimeter,  his  clothes  extracted  with  distilled  water  gave  an 
average  of  0.29  gm.  nitrogen  per  day  for  eighty-eight  days'  work. 

Lavonius  estimated  that  in  a  circus  athlete  the  loss  in  the 
sweat  was  1.8  gm.  nitrogen  per  day.  Zuntz  calculated  that  the 
loss  of  nitrogen  to  the  perspiration,  including  shed  epithelium,  is 
0.46  gm.  per  day. 

Atwater  and  Benedict  with  a  professional  bicyclist  twenty-eight 
years  of  age  and  62  kilos  in  weight,  placed  in  the  bicycle  ergometer 
for  four  hours,  found  that  the  heat  output  was  about  600  calories 
per  hour,  and  that  the  total  nitrogen  increase  was  roughly  pro- 
portional to  the  work  done. 

In  Sickness. — However,  it  has  been  shown  that  in  uremia,  a 
condition  of  poisoning  in  which  the  molecular  concentration  of 
the  blood  is  increased  as  a  result  of  impaired  kidneys,  the  sweat 
poured  out  may  contain  a  much  greater  proportion  of  nitrogenous 
material  than  that  from  hard  work.  It  is  reported  that  in  nephri- 
tis crystals  of  urea  have  actually  been  found  deposited  upon  the 
skin.  That  in  uremia  profuse  sweating  is  of  great  value  in  carry- 
ing off  nitrogenous  material  is  claimed  by  Bendix  (1904),  who 
was  able,  by  profuse  sweating  alone,  to  bring  to  normal  the  greatly 
depressed  freezing-point  of  the  blood  of  uremic  patients,  i.  e., 
to  reduce  its  molecular  concentration  to  normal.  It  is  claimed  by 
others  that  the  good  effects  are  due  to  the  removal  of  excess  of 
water  and  the  consequent  improvement  in  the  circulation  of  the 
kidneys.  At  any  rate,  in  uremia,  regardless  of  the  solids  excreted, 
diaphoresis  is  one  of  our  best  remedial  measures. 

Tachau  (191 2)  gave  one-hour  sweat-baths  to  nephritics  and 
determined  that  the  nitrogen  excreted  amounted  to  0.2  to  0.49 
gm.,  while  the  chlorides  were  1.3 1  to  2.05  gm.  Von  Noorden  says 
that  the  perspiration  of  nephritics  contains  a  maximum  of  1  to 


424  PHARMACOLOGY   AND   THERAPEUTICS 

1.3  gm.  of  urea  from  profuse  sweating,  and  this  is  too  little  to  be 
of  moment  to  the  kidneys.  Thus  sweating  in  nephritis  must  be 
considered  chiefly  of  use  in  removing  water  and  perhaps  chlorides 
rather  than  urea  or  other  nitrogenous  waste.  Therefore,  the  dia- 
phoresis should  be  employed  to  lessen  the  edematous  condition 
or  hydremic  plethora,  rather  than  to  remove  nitrogenous  waste. 

In  intestinal  putrefactive  toxemia  with  indicanuria,  indol  has 
been  detected  in  the  perspiration. 

In  a  simple  hot  bath,  as  in  the  more  elaborate  baths,  sweating 
may  be  profuse,  and  afterward  may  continue  for  many  hours  in 
excess  of  normal  if  the  person  remains  in  a  warm  room  or  in  bed. 

Therapeutics  and  Administration. — 1.  To  lower  temperature, 
in  mild  fevers — the  liquor  ammonii  acetatis,  2  drams,  or  spiritus 
aetheris  nitrosi,  1  dram.  The  effect  of  these  is  probably  almost 
nothing. 

2.  To  overcome  chill  or  cold — by  relieving  internal  congestion 
and  reestablishing  proper  cutaneous  circulation.  Hot  lemonade 
at  bedtime,  whisky  and  hot  water,  Dover's  powder,  and  a  hot 
bath  are  the  favorites,  with  extra  bed-clothes.  Dover's  powder 
is  in  extensive  use  by  both  physicians  and  the  laity  to  produce 
sweating,  especially  if  there  is  pain  or  restlessness.  But  unless  it 
is  given  with  a  copious  hot  drink  and  extra  bed-clothing  is  piled 
on,  the  chances  of  its  producing  profuse  sweating  are  very  small. 
It  is  given  in  5-  or  10-grain  doses,  and  is  often  followed  the  next 
morning  by  nausea,  headache,  and  a  feeling  of  lassitude. 

3.  To  lessen  obesity — exercise  with  heavy  woolen  clothing, 
Turkish  baths,  hot  baths,  restriction  of  liquids  ingested. 

4.  To  assist  the  kidneys  in  the  removal  of  accumulated  poisons, 
as  in  uremia,  and  possibly  in  gout,  rheumatoid  conditions,  eclamp- 
sia, and  other  toxemias.  Hot-pack,  vapor  baths,  etc.,  with  or 
without  pilocarpine,  and,  if  there  is  no  edema,  with  copious  drafts 
of  water. 

5.  To  lessen  edema  and  promote  the  absorption  of  dropsical 
effusions — hot-pack,  vapor  baths,  etc.,  with  dry  diet,  very  little 
water  being  ingested.  Sometimes  with  pilocarpine.  It  must  be 
understood,  of  course,  that  dropsical  fluid  disappears  by  way  of 
the  lymphatics  through  improvement  in  the  circulation;  edema 
fluid  may  be  reabsorbed  from  the  tissue-spaces  if  by  sweating  the 
blood  loses  water. 

6.  To  lessen  congestion  of  the  internal  eye  and  of  the  middle 
and  internal  ear — especially  by  pilocarpine. 

7.  To  hasten  the  outbreak  of  the  rash  in  measles  and  other  exan- 
themata.   Hot  baths  for  this  purpose  are  in  common  employment. 

8.  Local  sweating  with  high  temperature  is  used  in  chronic  rheu- 
matism, rheumatoid  and  gonorrheal  arthritis,  and  other  joint 


DIURETICS  425 

affections.  In  the  ordinary  baking-box  for  an  arm  or  a  leg,  such 
as  Bier's,  the  temperature  can  be  borne  for  half  an  hour  up  to  about 
1800  F.,  the  heat  of  a  baking  oven,  and  this  induces  a  marked 
hyperemia  of  the  limb,  with  profuse  perspiration.  With  the 
Sprague  apparatus,  in  which,  by  a  special  arrangement,  the 
evaporation  of  the  perspiration  keeps  pace  with  its  production  so 
that  there  is  never  any  visible  perspiration,  a  temperature  of 
3000  to  3500  F.,  the  so-called  "  superheated  air,"  can  be  borne 
without  discomfort  or  burning.  At  this  temperature,  if  a  drop 
of  water  should  collect  on  the  skin,  it  would  instantly  form  steam 
and  scald  the  skin.  A  limb,  or  even  the  whole  body  except  the 
head,  can  be  kept  at  this  temperature  for  fifteen  or  twenty  minutes, 
the  body-temperature  rising  from  1  to  4  degrees.  Cold  applica- 
tions should  be  kept  upon  the  head. 

DIURETICS 

A  diuretic  is  a  remedy  which  tends  to  promote  the  flow  of 
urine.    Diuresis  is  copious  flow  of  urine. 

The  kidney  is  a  highly  vascular  organ,  with  numerous  vaso- 
motor nerves  and  readily  influenced  arterioles.  Its  function  is 
to  preserve  the  normal  composition  of  the  body  fluids  by  ridding 
the  blood  of  certain  substances  which  are  present  in  excess  or  are 
not  normal  constituents,  hence  it  reacts  readily  to  changes  in  the 
blood  composition. 

The  blood  from  the  renal  artery  passes  along  the  afferent 
arterioles  into  the  capillaries  of  the  glomeruli,  and  there  loses  a 
certain  amount  of  water,  containing  substances  in  solution.  This 
escapes  through  the  endothelium  of  the  capillaries  and  their  cover- 
ing membrane  of  Bowman's  capsule  into  the  uriniferous  tubule; 
while  the  blood,  thus  concentrated,  leaves  the  glomerulus  by  an 
afferent  vein,  which  is  smaller  than  the  afferent  arteriole  (perhaps 
only  two-thirds  the  size).  "This  vein  divides  into  branches  after 
the  manner  of  an  artery,  and  from  these  arises  a  dense  network 
of  capillaries  which  everywhere  ramify  over  the  wall  of  the  urin- 
iferous tubule  "  (Quain) .  The  blood  in  the  capillaries  surrounding 
the  tubule  is,  therefore,  blood  with  a  diminished  total  of  dialyzable 
substances  and  concentrated  by  the  loss  of  water;  and  it  differs 
by  so  much  from  the  blood  in  the  capillaries  of  the  glomeruli. 

The  average  daily  urine  amounts  to  about  1500  c.c,  is  of  acid 
reaction,  and  contains  about  33  gm.,  i.  e.,  2.2  per  cent,  of  urea; 
while  the  blood  from  which  it  is  derived  is  alkaline  and  contains 
only  0.05  to  0.1  per  cent,  of  urea.  The  liquid  must,  therefore, 
undergo  striking  changes  in  its  passage  from  the  glomerular 
capillaries  to  the  ureter. 


426  PHARMACOLOGY  AND  THERAPEUTICS 

We  might  review  very  briefly  the  functions  of  the  different 
parts  of  the  kidneys : 

The  Glomerulus. — While  there  seems  to  be  no  doubt  that  this 
acts  largely,  if  not  almost  altogether,  as  a  mechanical  filter,  there 
is  some  evidence  that  its  cells  may,  in  addition,  select  and  secrete 
certain  of  the  elements  of  the  blood.  Brodie  believes  it  to  be  an 
expulsor  organ,  capable  of  expansion  and  contraction. 

The  Tubules. — That  the  tubules  have  the  power  to  reabsorb 
water  and  some  of  its  dissolved  substances  is  apparent  from  a 
number  of  experiments.  Cushny  showed  that  not  only  was  water 
absorbed,  but  that  there  was  a  differential  reabsorption  of  certain 
of  its  salts,  apparently  in  proportion  to  their  diffusibility,  e.  g., 
sodium  chloride  more  readily  than  sodium  sulphate.  He  found 
also  that  in  marked  diuresis  the  proportion  of  these  salts  in  the 
urine  was  more  nearly  equal;  and  he  figured  that  reabsorption 
failed  to  take  place  because  of  the  rapidity  of  the  passage  of  the 
liquid  through  the  tubules.  Moreover,  destruction  of  the  tubule 
cells  experimentally  or  by  disease  is  regularly  followed  by  increase 
of  urine  excretion. 

That  the  tubules  have  also  a  specific  secretory  power  is  sug- 
gested by  the  results  of  the  injection  of  sodium  sulphindigotate 
into  the  blood.  Within  a  minute  or  two  the  urine  secreted  is  blue, 
showing  that  the  pigment  passes  out  in  the  urine.  If  the  kidney 
is  at  once  removed  and  the  coloring-matter  fixed  by  perfusion 
with  alcohol,  microscopic  examination  shows  the  tubule  cells 
deeply  stained  with  blue,  while  the  glomeruli  are  not  stained  at 
all.  This  suggests  that  the  pigment  has  passed  through  the  tubule 
cells  (presumably  was  excreted)  rather  than  through  those  of  the 
glomerular  capillaries.  Again,  if  the  blood-pressure  is  reduced 
below4o  mm.  mercury  (below  which  pressure  all  urine  flow  ceases), 
the  cortex  alone  is  blue,  and  the  pigment  is  found  deposited  in 
granules  in  the  striated  epithelial  cells  and  the  lumen  of  the  first 
and  second  convoluted  tubules.  After  the  injection  of  uric  acid 
in  a  solution  of  piperazin  Starling  found  uric  acid  in  the  cells  and 
lumen  of  the  convoluted  tubules.  Nussbaum's  experiment  on 
the  reno-portal  vein  of  the  frog  and  some  experiments  on  poisoned 
kidneys  also  point  to  a  specific  secretory  power. 

By  injecting  acid  indicators  into  the  blood  it  may  be  shown 
that  the  glomerular  fluid  is  alkaline,  and  that  the  urine  becomes 
acid  in  the  convoluted  tubules;  if  it  is  hurried  through  the  tubules 
by  active  diuresis,  it  is  less  acid  and  may  be  alkaline. 

Without  entering  further  into  the  theories  of  kidney  action, 
which  are  not  yet  soundly  established,  and  can  be  read  up  in  any 
recent  book  on  physiology,  we  will  assume  that  the  function  of  the 
glomerulus  is  to  pass  from  the  blood  to  the  uriniferous  tubules 


DIURETICS  427 

large  quantities  of  an  alkaline  fluid  which  contains  urea,  chlorides, 
phosphates,  sulphates,  and  under  some  circumstances  sugar  and 
other  substances,  in  the  proportion  in  which  they  occur  in  the 
blood.  And  that  the  functions  of  the  tubules  are:  (1)  To  change 
the  reaction  of  the  glomerular  fluid  to  acid.  (2)  To  add  to-it  cer- 
tain substances  by  excretion,  such  as  urea,  uric  acid,  creatinin, 
urinary  pigment,  phosphates,  and,  under  certain  circumstances, 
water.  Hans  Meyer  says  that  no  known  diuretic  can  increase  the 
excretion  of  uric  acid  and  phosphates.  (3)  To  concentrate  the  urine, 
by  the  reabsorption  of  much  of  its  water  and  of  some  of  its  dis- 
solved substances.  These  are  reabsorbed  somewhat  according 
to  their  absorption  power,  i.  e.,  sodium  chloride  readily,  sulphates 
less  readily,  and  urea  not  at  all.  But  physiologic  conditions  pre- 
dominate over  physical,  for  foreign  substances,  though  readily 
diffusible,  such  as  potassium  iodide,  or  even  sodium  chloride  when 
this  is  in  excess,  will  be  passed  out  without  apparent  reabsorption. 

The  urine  is,  therefore,  made  up  essentially  of — (1)  water, 
(2)  such  dissolved  substances  as  have  been  removed  from  the 
blood  in  the  glomeruli  and  have  escaped  reabsorption,  and  (3) 
the  substances  excreted  by  the  tubule  cells.  Either  its  quantity 
or  its  quality  may  be  changed  by  an  alteration — (1)  in  the  con- 
stituents of  the  blood;  (2)  in  the  filtration  or  secretory  power  of 
the  glomeruli;  (3)  in  the  secretory  power  of  the  tubules;  or  (4)  in 
the  reabsorptive  power  of  the  tubules;  but  in  the  production  of 
diuresis  we  are  not  always  certain  which  of  these  are  the  factors 
involved. 

On  account  of  these  complex  factors  we  must  not  forget,  in 
treating  patients,  that  the  volume  of  the  urine  is  made  up  of 
water,  and  that,  therefore,  the  quantity  of  urine  excretion  is  not 
necessarily  a  measure  of  the  excrementitious  materials  that  are  being 
removed  from  the  body.  Indeed,  von  Noorden  states  that  a  con- 
centrated urine  may  carry  out  just  as  much  deleterious  matter  as 
one  less  concentrated.  As  the  normal  powers  of  healthy  kidneys 
are  vastly  more  than  sufficient  to  maintain  a  proper  blood  com- 
position, our  endeavor  in  disease  must  be  to  restore  the  kidney 
functions  or  to  minimize  the  amount  of  kidney  activity  required. 
We  cannot  confer  upon  the  kidneys  any  abnormal  powers,  or 
functions  new  to  kidney  tissue. 

From  these  remarks  it  will  be  seen  that  the  site  of  the  diuresis 
may  be  the  glomerulus  or  the  tubule,  or  both;  and  that  diuresis 
may  be  brought  about  by  : 

I.  Measures  which  increase  the  glomerular  fluid. 

(a)  By  increasing  the  blood-flow  through  the  kidney. 

(b)  By  lowering  the  osmotic  pressure  of  the  blood. 
II.  Measures  which  increase  the  tubular  secretion. 

III.  Measures  which  decrease  the  tubular  reabsorption. 


428  PHARMACOLOGY  AND  THERAPEUTICS 

I.  Measures  Which  Increase  the  Glomerular  Fluid. — (a)  By 

Increasing  the  Blood-flow  Through  the  Kidney. — It  is  evident  that 
constant  replacement  of  the  blood  of  the  kidneys  must  take  place 
or  the  urine  will  cease  to  flow.  It  is  evident,  also,  that  glomerular 
filtration  is  dependent  upon  the  maintenance  of  a  certain  capil- 
lary pressure,  for  experiments  show  that  when  general  arterial 
pressure  falls  below  about  40  mm.  of  mercury,  the  urine  ceases 
to  flow.  The  capillary  pressure  in  the  glomerulus  is  maintained 
by  the  general  arterial  pressure,  by  the  small  size  of  the  efferent 
vessel  of  the  glomerulus  as  compared  with  its  afferent  vessel,  and 
by  the  friction  of  the  second  set  of  capillaries.  About  the  pressure 
in  the  efferent  vessel,  and  about  its  dilatation  and  contraction,  we 
know  nothing;  but  it  is  found  by  experiment  that  even  a  moderate 
resistance  to  the  venous  outflow  from  the  kidney  checks  the  flow 
of  urine.  We  know  at  present,  therefore,  that  the  flow  of  urine  is 
readily  influenced  by  changes  in  the  amount  of  blood  passing  through 
the  kidneys;  and  that  this  amount  of  blood  is  regulated  by  the 
general  arterial  pressure,  by  the  caliber  of  the  kidney  arterioles, 
by  the  back  pressure  in  the  kidney  veins,  and  by  the  viscosity  of 
the  blood.  Digitalis  is  one  of  the  best  of  diuretics  in  conditions 
with  impaired  circulation.    (See  Digitalis.) 

The  kidney  arterioles  are  the  sluice-gates  to  the  capillaries. 
If  general  arterial  pressure  remains  constant,  dilatation  of  the 
kidney  arterioles  allows  a  greater  blood-flow  through  the  kidney 
capillaries,  and  contraction  of  the  arterioles  determines  a  lesser 
blood-flow.  If  the  caliber  of  the  arterioles  remains  constant,  a 
rise  in  general  arterial  pressure  causes  more  blood  to  pass  through, 
and  a  fall  in  pressure  causes  less  blood  to  pass  through. 

It  is  a  general  rule  that  diuresis  is  accompanied  by  dilatation 
of  the  kidney  arterioles  through  a  local  action,  and  in  most  instances 
it  is  observed  that  diuresis  is  dependent  upon  such  dilatation. 
But  there  are  exceptional  instances  where  absence  of  dilatation  of 
the  renal  arterioles  has  been  accompanied  by  diuresis,  or  where 
diuresis  has  failed  even  though  the  arterioles  were  dilated. 

In  experimental  vascular  nephritis  Pearce  reports  dilatation 
of  the  vessels  from  caffeine  and  from  5  per  cent,  sodium  chloride, 
but  diuresis  from  the  caffeine  only.  Also,  if  the  kidney  is  prevented 
from  expanding,  i.  e.,  the  vessels  not  allowed  to  dilate,  there  is  diu- 
resis from  caffeine,  but  not  from  various  diuretic  salts  and  dextrose. 

(b)  By  Lowering  the  Osmotic  Pressure  of  the  Blood. — If  sodium 
chloride,  sodium  acetate,  urea,  or  dextrose  in  hypertonic  solution 
is  injected  into  the  blood,  the  osmotic  pressure  of  the  blood  is  at 
once  raised.  Fluid  passes  to  it  from  the  tissues,  the  blood  swells 
up,  and  a  condition  of  hydremic  plethora  with  lowered  osmotic 
pressure  is  brought  about,  i.  e.,  the  quantity  of  blood  is  greater 


DIURETICS 


429 


than  normal,  the  tissues  or  tissue-spaces  having  been  drawn  upon 
for  a  diluting  fluid.  If  an  isotonic  or  hypotonic  saline  solution 
is  injected  into  a  vein,  swallowed,  or  administered  by  rectum,  this 
hydremic  plethora  results  without  the  imbibition  of  fluid  from 
the  tissues  or  tissue-spaces.  In  dropsy,  hydremic  plethora  results 
from  the  absorption  of  the  dropsical  fluid. 

In  hydremic  plethora,  under  the  influence  of  the  slightly 
raised  arterial  pressure  and  the  lessened  viscosity  of  the  blood, 
this  swollen  volume  of  blood  tends  to  promote  rapid  blood-flow, 
and,  as  a  consequence,  to  favor  transudation  of  the  excess  of  fluid 
through  capillaries.  The  kidney  capillaries  are  the  ones  by  which 
the  body  gets  rid  of  excessive  fluid;  therefore  if  the  kidneys  are 
functionating  properly,  there  is  diuresis,  and  the  excess  of  water 
with  certain  dissolved  materials  is  rapidly  got  rid  of.  Hydremic 
plethora  and  its  resulting  diuresis  may  be  the  consequence  of  the 
absorption  of  dropsical  fluid,  as  under  the  administration  of 
digitalis. 

It  may  be  produced  intentionally  by  the  ingestion  of  water, 
or  of  solutions  of  dialyzable  substances,  so  that  these  are  diuretic. 

Of  dialyzable  substances,  those  with  a  pronounced  diuretic 
action  are: 

(a)  Inorganic  Salts. — Sodium  sulphate,  sodium  chloride,  so- 
dium or  potassium  bicarbonate,  magnesium  salts.  Except  the 
bicarbonates,  these  are  not  employed  as  diuretics. 

(b)  Organic  Salts. — The  acetates,  citrates,  and  tartrates, 
which  break  down  into  carbonates  in  the  blood.  They  are  po- 
tassium acetate,  potassium  citrate,  potassium  bitartrate,  potassium 
and  sodium  tartrate,  magnesium  citrate,  liquor  ammonii  acetatis, 
liquor  ferri  et  ammonii  acetatis  (Basham's  mixture).  The  best  of 
these  is  potassium  acetate. 

(c)  Urea,  Dextrose. 

All  these  substances  tend  to  have  an  effect  upon  the  urination 
in  direct  proportion  to  the  osmotic  pressure  which  they  exert. 
In  hydremic  plethora,  if  the  kidneys  are  not  functionating  well, 
as  in  chronic  nephritis,  the  excess  of  water  tends  to  transude 
through  the  systemic  capillaries  and  to  favor  the  production  of 
edema  and  dropsy. 

Water. — Ordinary  drinking-water  is  hypotonic,  and  is  prac- 
tically unabsorbed  by  the  stomach.  But  it  imbibes  salts  from  the 
food  or  mucus,  or  from  the  superficial  cells  of  the  alimentary  tract, 
or  takes  up  the  sodium  chloride  which  is  formed  in  the  duodenum 
by  the  neutralization  of  the  hydrochloric  acid  of  the  gastric  juice. 
Hence  it  becomes  a  salt  solution,  and,  instead  of  passing  on 
through  the  intestine  to  the  rectum,  is  absorbed.  Therefore  when 
water  is  ingested  it  does  not  normally  pass  out  with  the  feces;  and 
under  ordinary  conditions  of  absorption,  no  matter  how  much  is 


430  PHARMACOLOGY  AND  THERAPEUTICS 

drunk,  does  not  produce  a  movement  of  the  bowels  (Starling). 
So  the  ingestion  of  large  quantities  of  water  leads  to  a  condition  of 
hydremic  plethora,  which  results  in  increased  urination.  Water 
is,  therefore,  diuretic,  and  in  its  elimination  tends  to  carry  out 
certain  dissolved  substances,  especially  urea,  sulphates,  and  phos- 
phates. Leonard  Hill  says  it  only  washes  out  the  urea  stored  in 
the  tissues  and  does  not  provoke  increased  destruction  of  tissue 
protein ;  but  Hawk  has  gathered  some  evidence  that  copious  water 
drinking  results  not  only  in  a  removal  of  stored-up  urea,  but  also 
in  increased  protein  destruction. 

The  body  has  a  great  capacity  for  the  storing  of  water,  so  that 
even  when  the  excretory  apparatus  is  impaired,  excessive  amounts 
of  water  can  be  taken  for  many  days  before  dropsy  sets  in.  In 
these  cases  it  is  evident  that  a  diuretic  is  indicated  before  dropsy 
is  apparent.  But  water  should  not  be  given,  for  in  dropsical  con- 
ditions large  quantities  of  water  serve  only  to  increase  the  already 
"water-logged"  condition  of  the  patient. 

As  a  consequence  of  introducing  dialyzable  substances  physio- 
logically foreign  to  the  blood,  diuresis  may  result.  The  kidney  is 
exceedingly  sensitive  to  the  presence  of  certain  foreign  substances 
in  the  blood,  e.  g.,  potassium  iodide,  sodium  sulphate,  magnesium 
sulphate,  and  may  excrete  them  even  without  hydremic  plethora. 
But  whether  this  work  is  done  by  the  glomerulus  or  the  tubules 
has  not  been  fully  determined. 

II.  Measures  Which  Increase  the  Tubular  Secretion,  and 
III.  Measures  Which  Decrease  the  Tubular  Absorption. — 
Between  these  two,  we  cannot  at  present  discriminate.  The 
diuretics  which  act  upon  the  tubules,  however,  may  be  divided 
for  practical  purposes  into — 

i.  Those  which  are  non-irritant  to  the  kidney,  and  conse- 
quently in  the  larger  doses  do  not  produce  inflammation — caffeine, 
theobromine,  theophylline,  diuretin,  agurin.    (See  Caffeine.) 

2.  Those  which  are  irritant,  and  in  overdose  may  produce 
inflammation.    They  are : 

(a)  Volatile  oils,  and  resinous  or  aromatic  drugs,  especially 
the  oils  of  sandalwood,  juniper,  turpentine,  the  balsam  of  copaiba, 
and  the  drugs  buchu,  cubeb,  kava-kava,  matico,  uva  ursi,  and 
cantharis.  These  are  less  prescribed  as  diuretics  than  as  urinary 
antiseptics.    The  oil  of  juniper  is  present  in  "gin." 

(b)  Certain  drugs  which  contain  irritant  glucosides  and  are 
mostly  used  in  the  form  of  infusion;  for  example,  scoparius  or 
broom,  which  contains  scoparin,  and  asparagus,  which  contains 
asparagin. 

(c)  Calomel. — A  dose  of  calomel  at  the  beginning  of  diuretic 
treatment  will  often  hasten,  or  at  least  appear  to  hasten,  the  on- 
set of  diuresis.    This  is  particularly  true  in  venous  stagnation.    It 


DIURETICS  431 

may  act  by  irritating  the  kidney  cells;  but  its  action  is  more 
probably  due,  not  to  direct  diuresis,  but  to  the  relief  of  the  kidneys 
through  the  removal  of  fluid  by  the  bowels. 

There  are  some  other  substances,  such  as  urotropin,  which  are 
urinary  antiseptics  rather  than  active  diuretics. 

To  compare  the  various  diuretics,  Raphael  (1894)  placed  him- 
self on  a  uniform  diet  for  a  long  period,  the  daily  allowance  of 
fluid  being  1180  c.c.  His  twenty-four-hour  urine  ranged  between 
750  and  960  c.c.  When,  in  addition  to  his  uniform  diet,  he  took 
diuretics,  his  urine  increased  as  follows : 

Increase. 

0.4  gm.  oil  of  turpentine 11  per  cent 

0.2  gm.  oil  of  juniper  +  iooo  c.c.  water in 

0.5  gm.  caffeine  and  sodium  salicylate 42 

0.5  gm.  theobromine  and  sodium  salicylate  (diuretin)     2 

1.5  gm.  theobromine  and  sodium  salicylate 14 

3.0  gm.  theobromine  and  sodium  salicylate 53 

30.0  gm.  sugar  of  milk 34 

1000.0  c.c.  water 100 

1000.0  c.c.  carbonic  water 73 

1000.0  c.c.  beer 100 

1000.0  c.c.  claret 80 

1000.0  c.c.  milk 153 

As  a  general  rule,  the  following  things  are  true  about  the  urine 
of  diuresis : 

1.  The  filtered  substances,  urea  and  salts,  are  increased  in 
proportionally  greater  amount  than  the  secreted  substances,  uric 
acid,  creatinin,  pigment,  etc.,  and  there  may  be  no  increase  in  the 
latter  substances  at  all. 

2.  According  to  Hans  Meyer,  the  excretion  of  uric  acid  and 
phosphates  is  not  increased  by  any  known  diuretic.  But  it  would 
seem  that  the  excretion  of  phosphates  is  increased  by  water 
(Hawk),  and  possibly  that  of  uric  acid  by  atophan  and  piperazine. 

3.  Substances  which  are  ordinarily  reabsorbed  are  passed  out 
in  greater  proportion  to  the  other  substances  than  normally,  their 
proportional  reabsorption  being  prevented  either  by  the  more 
rapid  flow  which  takes  place  through  the  tubules,  or  by  impair- 
ment of  the  reabsorbing  power  of  the  cells. 

4.  Frequently,  for  the  first  day  or  two  of  diuresis  there  is  a 
great  increase  in  the  amount  of  some  of  the  solids  excreted,  as  if 
there  had  been  accumulation  of  these  in  the  body  and  they  were 
being  washed  out.  Magnus  says  that  for  each  salt  (substance) 
there  is  a  "secretion  threshold,"  a  certain  degree  of  concen- 
tration in  the  blood,  above  which  an  increase  leads  to  the  elimina- 
tion of  the  excess  with  an  increased  secretion  of  water.  It  may  be 
that  in  diuresis  the  level  of  this  "secretion  threshold"  is  lowered. 

5.  Without  abundant  supply  of  water  there  is  no  diuresis. 


432 


PHARMACOLOGY  AND  THERAPEUTICS 


Fig.  52. — Drawing  made  to  scale  from  tracings  taken  from  a  dog  by  C.  C.  Lieb. 
Horizontal  line  of  figures,  time  in  minutes.  Black  line,  arterial  pressure;  dotted 
line,  urine  flow.  The  close  relation  between  general  blood-pressure  and  urine  flow 
is  striking.  The  drugs,  in  the  order  used,  with  dose  per  kilo,  are:  Cajjeine,  2  mg., 
urine  little  affected.  Theophylline  acct-sodium,  3  mg.,  urine  much  increased. 
Spirit  of  nitroglycerin,  0.3  c.c,  urine  decreased.  Theobromine  sodium  salicylate, 
3  mg.,  urine  increased.  Caffeine  and  sodium  benzoate,  4  mg.,  continues  theo- 
bromine effect.  Animal  bled,  20  c.c.  per  kilo,  great  fall  in  urine.  Saline  infusion, 
25  c.c.  per  kilo,  great  increase.  Camphor  in  oil,  20  mg.,  decided  fall.  Pituitary 
extract,  0.1  c.c,  fall  followed  by  rise.  Adrenaline  solution,  0.1  c.c,  fall  followed  by 
rise.  Tincture  of  cantharides  was  then  given  in  amounts  large  enough  to  produce 
inflammation  of  the  kidney. 


DIURETICS  433 

Therapeutics  of  Diuresis. — The  two  great  uses  of  diuresis  are — 
(i)  To  promote  the  elimination  of  poisons  formed  in  the  body,  and 
(2)  to  cause  the  removal  of  dropsy. 

1.  To  Promote  the  Elimination  of  Poisons.— Assuming  that  the 
kidneys  are  functionally  good,  diuresis  brought  about  in  any 
manner  tends  to  increase  the  excretion  of  any  dialyzable  substance 
in  the  blood;  for  the  water  in  passing  out  must  carry  with  it  some 
of  each  of  the  filterable  substances  of  the  blood.  If  the  poisons 
are  not  filterable,  they  pass  out  in  the  urine  only  if  the  tubule  cells, 
or  perhaps  the  cells  of  the  glomeruli,  can  take  them  from  the  blood 
and  excrete  them.  The  tubules  are  exceedingly  sensitive  to  foreign 
substances  in  the  blood,  and  are  probably  competent  to  excrete 
many  of  the  unusual  deleterious  substances  of  the  body,  such  as 
toxins  of  disease  or  abnormal  products  of  metabolism;  but  we 
have  no  satisfactory  data  to  indicate  just  how  much  of  a  role 
they  do  play  in  such  elimination.  To  promote  elimination  of 
toxic  substances  large  drafts  of  water  are  given. 

When  the  kidneys  are  diseased,  as  in  chronic  nephritis  with 
uremia,  the  utility  of  this  or  that  diuretic  is  purely  experimental. 

2.  To  cause  the  removal  of  dropsy  and  edema, — i.  e.,  the  removal 
of  fluid  from  the  potential  tissue-spaces.  The  treatment  of  drop- 
sical or  edematous  conditions  is  of  the  greatest  interest  from  a 
diuretic  point  of  view.  There  are  four  great  causes  of  edema,  viz., 
venous  engorgement,  kidney  impermeability,  tissue  retention,  and 
abnormal  general  capillary  permeability.  As  a  rule,  a  combination 
of  diuretics  is  advised,  and  a  diminution  of  the  water  intake. 

(a)  Venous  engorgement  has  been  discussed  at  length  under 
Digitalis.  At  times  the  best  results  are  obtained  with  digitalis  to 
activate  the  circulation,  and  diuretin  or  a  saline  such  as  potassium 
acetate  to  dilate  the  kidney  arterioles. 

(b)  Kidney  impermeability  is  a  difficult  thing  to  overcome, 
because  it  depends  on  kidney  disease.  The  impermeability  for 
salts,  urea,  uric  acid,  water,  etc.,  may  depend  largely  on  the  type 
of  affection  of  the  kidney.  Much  experimental  work  has  been 
done  on  forms  of  acute  nephritis  produced  by  poisons.  Thus 
poisons  affecting  the  tubular  epithelium  are  uranium  nitrate, 
mercuric  chloride,  and  the  alkaline  chromates;  poisons  affecting 
the  glomerular  capillaries  are  arsenic,  cantharidin  and  rattlesnake 
venom;  and  a  poison  that  will  affect  both  capillaries  and  tubules 
is  diphtheria  toxin.  The  glomerular  capillaries  seem  to  be  affected 
beyond  all  other  capillaries,  probably  by  a  remote  local  action  in 
the  elimination  of  the  poisons. 

In  the  experimental  acute  tubular  nephritis  there  is  copious 
urination,  increased  by  most  diuretics.    In  the  experimental  acute 
glomerular  nephritis  there  is  no  polyuria  and  deficient  response  to 
28 


434  PHARMACOLOGY  AND  THERAPEUTICS 

diuretics.  In  either  case,  after  a  few  days'  exposure  to  the  poison, 
the  lesions  tend  to  extend  and  become  combined;  but  when  the 
poison  is  stopped,  the  kidneys  heal  and  do  not  show  the  lesions  of 
chronic  nephritis  (Pearce). 

When  the  human  kidneys  are  impaired,  as  in  nephritis,  there 
may  be  abnormal  retention  of  various  substances,  i.  e.,  the  kidney 
loses  its  power  to  excrete  to  the  full  degree.  According  to  von 
Noorden,  in  acute  nephritis  the  following  substances  continue  to 
be  well  excreted,  viz.,  uric  acid,  the  xanthine  bases,  aromatic 
bodies,  ammonia,  amido-acids,  chlorides,  and  carbonates;  while 
among  those  which  are  excreted  with  difficulty  and  tend  to  be 
retained  are  urea,  creatinin,  urinary  pigment,  hippuric  acid,  phos- 
phates, inorganic  sulphates,  and  in  some  cases  water. 

In  chronic  nephritis  with  edema  we  have  little  information  to 
guide  us  in  our  choice  of  diuretics,  and  our  best  plan  is  to  use  a 
saline  diuretic  with  one  of  the  caffeine  series,  such  as  diuretin. 
Pearce  has  shown  that  kidney  injury  alone  is  insufficient  to  cause 
edema.  There  must  be,  in  addition,  general  capillary  permeabil-' 
ity  and  hydremic  plethora. 

(c)  Tissue  retention  of  water  as  a  cause  of  edema  is  a  subject 
not  fully  understood.  In  chronic  edematous  states  it  is  customary 
to  put  the  patient  on  a  diet  very  low  in  sodium  chloride,  the  so 
called  " salt-free"  or  ''salt-poor"  diet.  This  reduces  the  sodium 
chloride  in  the  urine,  but  seems  to  make  little  alteration  in  the 
percentage  of  sodium  chloride  in  the  blood-plasma.  It  is,  how- 
ever, an  effective  measure  in  many  cases. 

(d)  Abnormal  permeability  of  the  capillaries  of  the  body  is  un- 
doubtedly the  result  of  poisons,  as  in  arsenic  poisoning  and  uremia. 

It  is  to  be  remembered  that  diuresis  requires  water  as  its 
medium,  so  that  to  promote  the  elimination  of  poisons,  copious 
drafts  of  water  should  be  administered  with  the  diuretic.  If, 
however,  there  is  edema  or  any  degree  of  water  retention,  all 
fluids  should  be  restricted. 


ANTIPYRETICS 

Antipyretics  are  remedies  which  tend  to  reduce  the  tempera- 
ture in  fever.  Many  remedies  which  have  this  property  are  con- 
sidered elsewhere,  because  the  antipyretic  property  is  not  the 
dominant  one;  for  example,  whisky  and  digitalis.  The  reduction 
of  temperature  may  be  brought  about  by  cold  or  by  drugs. 

Cold. — Some  of  the  methods  for  applying  cold  are :  The  cold 
bath,  the  cold-pack  and  the  drip  sheet ;  and  for  local  use  the  cold 
compress,  the  ice-water  coil  or  ice-bag,  the  rectal  irrigation  with 
ice-water,  the  cold  spinal  douche,  etc. 

The  cold  bath  is  employed  in  typhoid  fever.    In  the  tub-bath 


THE    ANALGESIC    ANTIPYRETICS  435 

the  patient  is  covered  with  a  sheet  and  lifted  into  a  bath  contain- 
ing water  at  about  700  F.  The  primary  shock  is  less  if  he  is  placed 
in  the  bath  at  850  or  900  F.,  and  the  water  cooled  rapidly  to  700  F. 
by  the  addition  of  ice.  The  head  should  be  cooled  with  ice-cold 
compresses,  and  the  body  rubbed  vigorously  during  the  bath.  A 
preliminary  dose  of  whisky  tends  to  dilate  the  cutaneous  vessels 
and  increase  the  output  of  heat.  The  bath  is  continued  for  from 
ten  to  fifteen  minutes.  The  bed-bath  is  made  by  having  the 
patient  on  a  large  piece  of  rubber  sheeting,  of  which  the  edges  are 
raised  over  pillows  or  rolled-up  sheets.  Cold  water  is  poured  in 
around  the  patient,  ice  added,  and  the  patient 's  body  soused  with 
the  water  by  means  of  a  large  sponge. 

In  the  cold-pack  one  or  two  sheets  are  wrung  out  of  cold  water 
and  wrapped  around  the  patient,  the  first  layer  of  sheet  passing 
beneath  the  arms  and  being  tucked  between  the  legs.  The  patient 
lies  on  a  blanket,  in  which  he  is  then  completely  enveloped  up  to 
the  neck.  After  fifteen  minutes  these  coverings  are  removed.  If 
desired,  the  sheets  may  again  be  wrung  out  of  cold  water  and  the 
process  renewed.  When  the  drip  sheet  is  used  as  an  antipyretic 
measure,  the  patient  is  wrapped  in  a  sheet  in  the  same  manner  as 
above,  but  sits  up  and  has  cold  water  poured  over  him.  These 
methods  of  applying  cold,  whether  followed  by  a  good  reaction 
or  by  shivering,  cause  an  increase  in  the  viscosity  of  the  blood 
(Determann,  Austrian). 

Antipyretic  Drugs 
The  group  known  as  antipyretics  includes  only  those  drugs 
whose  most  pronounced  property  is  to  reduce  the  temperature 
of  fever.  It  does  not  include  aconite,  alcohol,  digitalis,  phenol, 
and  other  drugs  which  possess  the  power  to  lower  temperature  in 
fever,  but  have  other  important  activities  that  lead  us  to  class 
them  elsewhere.  For  convenience,  the  essential  antipyretics  may 
be  divided  into  three  therapeutic  groups,  viz.,  the  analgesics,  the 
antimalarials,  and  the  antirheumatics. 

THE  ANALGESIC  ANTIPYRETICS 

The  official  ones  are  antipyrine,  acetanilid,  and  phenacetin. 
Some  of  the  quinoline  derivatives,  among  the  so-called  coal-tar 
drugs,  have  been  employed  largely  as  antipyretics  (kairin,  thallin, 
etc.),  but  have  been  discarded  in  favor  of  more  certain  remedies. 

Antipyrina,  antipyrine,  phenyl-dimethyl-pyrazolon, 

NC6HS 
CH3N,/     \co 


CHsC'  J  CH 


43^  PHARMACOLOGY  AND  THERAPEUTICS 

is  freely  soluble  in  water  and  alcohol,  and  has  a  slightly  bitter 
taste.  It  is  a  body  closely  resembling  the  alkaloids,  and  is  pre- 
cipitated by  tannic  acid,  alkalies,  and  some  other  alkaloidal 
reagents.  With  calomel  it  forms  a  poisonous  compound.  With 
spirit  of  nitrous  ether  or  other  nitrites  it  gives  a  deep-green  color 
(iso-nitroso-antipyrine) ;  with  ferric  salts  a  deep  red;  with  chloral 
hydrate,  naphthol,  phenol,  and  sodium  salicylate  it  liquefies;  with 
caffeine,  quinine,  and  some  other  alkaloids  it  forms  soluble 
double  salts.  Dose,  4  grains  (0.25  gm.).  For  local  application  it 
is  employed  in  5  to  25  per  cent,  aqueous  solution.  Close  relatives 
are  pyramidon,  dimethyl-amidophenyl-dimethyl  pyrazolon,  and 
salipyrine,  antipyrine  salicylate. 

Acetanilidum,  acetanilid,  phen-acetamide,  C6H5.NH.CH3CO, 
has  a  slightly  biting  taste,  and  is  soluble  in  180  parts  of  water  and 
in  2.5  of  alcohol.  Its  solubility  in  water  is  increased  by  acids  and 
decreased  by  alkalies.    Dose,  4  grains  (0.25  gm.). 

An  official  preparation  is  compound  acetanilid  powder  (pulvis 
acetanilidi  compositus),  which  contains  acetanilid,  7  parts,  caf- 
feine, 1  part,  and  sodium  bicarbonate,  2  parts.  Close  relatives 
of  acetanilid  are  exalgine,  methyl-acetanilid,  and  salophen,  ace- 
tanilid-salicylic  acid. 

Acet-phenetidin,  C6H4.OC0H5.NH.CH3CO,  more  familiarly 
known  under  the  proprietary  name  phenacetin,  is  a  derivative  of 
phenol.  It  is  soluble  in  925  parts  of  water  and  12  of  alcohol,  and 
is  almost  tasteless.  The  chemic  formula  shows  that  phenacetin 
might  properly  be  called  oxyethyl-acetanilid,  but  it  is  not  a  direct 
derivative  of  acetanilid,  and  may  better  be  placed  in  a  separate 
group  with  other  phenetidin  compounds.  It  is  not  readily  soluble 
in  water.  Dose,  8  grains  (0.5  gm.).  The  other  phenetidin  com- 
pounds worthy  of  note  are  lactophenin,  a  lactic-acid  derivative; 
malakin,  a  salicylic-acid  derivative ;  and  apolysin  and  citrophen, 
the  mono-  and  tri-phenetidin  citric  acids. 

Pharmacologic  Action. — These  drugs  all  reduce  temperature 
in  the  same  way,  are  all  analgesic,  are  all  nerve  sedatives,  and  are 
all  antiseptic.  Their  antiseptic  action  is  mild,  but  is  the  same  in 
kind  as  that  of  the  phenol  group  of  antiseptics,  to  which  they  are 
closely  related  chemically.  Their  antipyretic  action  is  powerful, 
as  exhibited  in  the  reduction  of  temperature  in  the  infectious 
fevers.  Their  analgesic  action  is  chiefly  shown  in  headache  and 
nerve  and  muscle  pains. 

Locally,  antipyrine  differs  from  the  others  in  that  a  10  to  25 
per  cent,  solution  applied  to  a  mucous  membrane  acts  mildly  like 
cocaine,  inducing  vasoconstriction  with  shrinkage  of  the  mem- 
brane and  the  checking  of  small  hemorrhages,  and  lessening  pain. 
Acetanilid  is  slightly  irritant  locally,  and  phenacetin  is  bland. 


THE    ANALGESIC   ANTIPYRETICS  437 

The  Antipyretic  Effect. — It  seems  probable  that  in  many  cases 
hyperthermy  or  fever  is  a  protective  reaction  on  the  part  of  the 
body,  and  in  these  cases  moderate  degrees  of  fever  require  no 
antipyretic  treatment.  There  are  some  cases,  however,  in  which 
even  mild  degrees  of  fever  seem  disadvantageous,  and  others  in 
which  the  protective  fever  reaction  overshoots  the  mark  and  pro- 
duces a  high  and  dangerous  body-temperature,  and  it  is  in  these 
that  antipyretic  measures  are  indicated. 

In  fever  the  temperature  may  be  reduced  either  by  lessened 
production  of  heat  or  by  increased  output  of  heat,  or  by  both. 
The  tendency  of  the  body  is  to  keep  itself  at  a  normal  tempera- 
ture. If  the  body  is  too  warm,  there  is  a  dilatation  of  cutaneous 
blood-vessels  and  an  outpouring  of  sweat,  so  that  the  body  will 
undergo  heat-loss  by — (i)  Radiation  of  heat,  more  heated  blood 
from  the  interior  being  brought  to  the  surface;  and  (2)  the  evapo- 
ration of  sweat.  At  the  same  time  there  is  a  tendency  to  lessened 
muscular  activity  with  diminished  heat-production.  This  com- 
bination of  lessened  heat-production  and  greater  heat-dissipation 
tends  to  bring  the  overheated  body  to  a  normal  temperature. 

If,  on  the  contrary,  the  body  is  too  cool,  there  is  stimulus  to 
greater  muscular  activity,  the  muscular  act  of  shivering  takes 
place,  sweating  stops,  and  the  cutaneous  vessels  are  contracted. 
So  there  are  greater  heat-production  and  lessened  heat-dissipa- 
tion, and  the  too  cool  body  becomes  warmed. 

This  heat-production  and  heat-dissipation  are,  to  a  certain 
extent,  under  the  control  of  some  central  structures  at  the  base 
of  the  brain,  spoken  of  collectively  as  the  heat-regulating  center, 
and  the  function  of  this  center  is  to  keep  the  body-temperature 
normal.  Any  variations  from  the  normal  affect  this  center;  and 
it  at  once  sends  out  impulses  which  influence  the  mechanisms  for 
the  production  or  the  dissipation  of  heat,  as  may  be  needed. 

In  active  muscular  exercise  much  heat  is  produced;  but 
through  the  heat-regulating  mechanism  heat-dissipation  is  in- 
creased to  correspond,  so  that  the  temperature  scarcely  rises,  and 
if  it  does,  is  soon  restored  to  normal.  The  extra  loss  of  heat  is 
brought  about  by  dilatation  of  the  cutaneous  vessels  and  sweating. 

But  in  some  of  the  infectious  fevers  that  have  been  studied 
the  heat-production  has  been  found  very  little  increased,  and 
the  hyperthermy  to  be  due  to  the  failure  of  the  heat-dissipating 
mechanisms  to  do  their  work.  For  example,  in  one  case  of  malaria 
Liebermeister  estimated  the  increase  in  heat-production  during 
the  hot  stage  to  be  21  to  24  per  cent.,  much  less  than  the  increase 
during  active  exercise;  but  during  the  malarial  chill,  owing  to  the 
muscular  activity  of  vigorous  shivering,  the  heat-production  rose 
147  per  cent.    At  the  same  time,  owing  to  the  constriction  of  the 


43&  PHARMACOLOGY  AND  THERAPEUTICS 

cutaneous  vessels,  the  mechanisms  for  heat-dissipation  were  in 
abeyance.  It  would  seem  in  such  cases  that  the  fever  results 
from  the  failure  of  the  heat-regulating  center  to  make  the  heat- 
loss  keep  pace  with  the  heat-production.  Whether  or  not  the 
toxins  of  the  disease  affect  the  center  directly  is  still  a  question. 

A  chill  is  considered  to  be  the  result  of  surface  cooling  from 
constriction  of  the  cutaneous  arterioles,  the  skin  being  the  site 
of  the  nerve-endings  through  which  temperature  changes  are 
perceived.  In  a  chill,  shivering  is  the  heat-producing  response  of 
the  regulators  to  the  cold  at  the  surface  rather  than  to  general 
body-temperature.  The  subsequent  fever  results  from  this 
excessive  heat-production  at  a  time  when  the  skin  vessels  are  still 
constricted  and  sweating  absent,  i.  e.,  when  heat-loss  is  at  a 
minimum. 

In  those  of  the  infectious  fevers  which  have  been  studied  in 
this  regard  there  is  a  great  increase  in  the  nitrogen  elimination 
during  the  fever,  but  no  material  increase  in  the  amount  of  fats 
and  carbohydrates  oxidized,  as  shown  by  the  eUmination  of  C02; 
therefore  heat-production  is  not  greatly  increased.  Just  the 
opposite  condition  is  found  in  active  exercise,  in  which  there  is 
great  increase  in  the  eUmination  of  C02  and  only  a  moderate 
increase  in  the  nitrogen  of  the  urine. 

Liebermeister  has  likened  this  heat-regulating  center  to  the 
heat-regulator  of  a  room.  The  heat-regulator  is  set  at  a  certain 
temperature;  if  the  room  gets  warmer,  the  mercury  rises  or  a 
metallic  band  expands,  and  by  making  an  electric  connection 
operates  on  one  or  more  dampers  in  the  furnace  so  that  the  fire 
burns  less  briskly,  or  shuts  down  the  registers  so  that  the  room 
receives  less  heat.  If  the  temperature  of  the  room  falls  below  that 
at  which  the  regulator  is  set,  the  dampers  or  registers  are  opened 
and  more  heat  comes  into  the  room.  Now,  to  carry  out  the 
analogy,  the  heat-regulating  center  in  the  human  body  may  be 
thought  of  as  being  normally  set  for  a  temperature  between  980 
and  990  F.  If  the  temperature  goes  up  a  degree  or  two,  the  center 
sends  out  impulses  which  result  either  in  a  lessening  of  heat-pro- 
duction, i.  e.,  by  diminution  in  muscular  and  circulatory  activity, 
or  an  increase  in  heat-loss,  i.  e.,  by  dilatation  of  the  cutaneous 
vessels  and  sweating.  On  the  contrary,  if  the  temperature  falls 
adegree  or  two,  the  heat-production  may  be  increased  by  muscular 
activity,  shivering,  etc.,  or  the  heat-loss  diminished  by  contrac- 
tion of  the  cutaneous  vessels  and  the  stoppage  of  sweating. 

The  temperature-regulating  center  has  little  discriminating 
power,  and  a  surface  chill  may  induce  the  center  to  constrict  the 
vessels  and  lessen  heat-loss,  and  at  the  same  time  to  increase  the 
production  of  heat,  so  that  fever  may  result.    To  what  extent  the 


THE   ANALGESIC   ANTIPYRETICS  439 

body  reaction  which  results  in  fever  is  beneficial  or  harmful,  we 
are  not  yet  able  to  state.  Recently  certain  infections  seem  to  have 
been  cured  by  the  repeated  artificial  production  of  a  chill  with 
high  fever. 

In  some  fevers  the  regulating  center  may  lose  its  control  at 
certain  times  of  the  day  only.  In  tuberculosis  there  is  a  tendency 
to  afternoon  fever,  accompanied  by  headache,  discomfort,  and 
weakness  from  failure  of  heat-loss,  while  at  night  there  may  be  an 
overaction  of  the  mechanism  for  cooling,  with  diminished  metabo- 
lism and  the  production  of  profuse  sweat,  the  result  being 
chilling  of  the  surface  (cold  night-sweats)  and  a  fall  of  tempera- 
ture to  subnormal.  Frequently,  in  tuberculosis  fever  cases,  the 
morning  temperature  is  normal  and  the  patient  feels  at  his  best 
at  that  time.  But  in  tuberculosis  the  center  is  incompetent,  so 
that  a  slight  exertion  tends  to  produce  fever  at  any  time. 

In  malaria  there  is  a  severe  chill  with  contraction  of  the  skin 
vessels  and  the  generation  of  much  heat  (by  shivering).  After  a 
time  this  results  in  great  fever  and  discomfort,  the  contraction 
of  the  skin  vessels  and  the  absence  of  sweating  preventing  heat- 
loss.  But  presently  the  center  gains  control,  and  great  activity 
of  the  cooling  mechanism  follows.  The  result  is  dilatation  of  the 
skin  vessels  and  profuse  sweating,  with  a  fall  in  temperature 
to  normal  or  even  subnormal,  and  the  restoration  of  the  patient's 
comfort  till  the  next  chill  comes  on  a  day  or  two  later. 

In  a  continuous  fever  like  typhoid,  apparently  the  heat- 
regulating  center  is  set  at  a  high  point,  1020  F.,  1030  F.,  1040  F. 
The  center  is  just  as  sensitive  to  changes  as  ordinarily,  for  shiver- 
ing follows  a  drop  of  2  or  3  degrees  in  the  temperature,  and  sweat- 
ing results  from  a  rise  of  1  or  2  degrees.  But  the  temperature  at 
which  the  center  tends  to  keep  the  body  is  not  98. 6°  F.,  but 
1020  F.,  1030  F.,  or  1040  F.,  as  the  case  may  be. 

But  even  in  typhoid  fever  there  is  a  tendency  to  a  morning 
remission  of  temperature,  with  a  rise  to  the  highest  point  in  the 
afternoon  or  evening.  And  it  would  seem  as  if,  preceding  the  rise 
in  temperature  in  these  cases,  the  heat-regulator  is  affected  by  the 
poisons  of  the  disease,  so  that  it  allows  the  temperature  to  rise 
above  normal;  but  that,  at  a  certain  point,  the  center  gathers 
itself  together  and  is  able  to  assert  itself  and  regain  its  control, 
and  the  temperature  is  brought  back  toward  normal.  This 
makes  a  daily  rhythm. 

Action  of  Drugs. — A  drug  may  tend  to  lessen  the  temperature 
in  fever  by  decreasing  metabolism,  as  quinine,  by  lessening  the 
activity  of  the  circulation, 'as  veratrum,  by  dilating  the  cutaneous 
vessels,  as  whisky,  or  by  inducing  perspiration,  as  solution  of 
ammonium  acetate.    But  antipyrine,  acetanilid,  phenacetin,  and 


44°  PHARMACOLOGY  AND  THERAPEUTICS 

their  allies  act  centrally,  and  they  result  in  a  lowering  of  the  tem- 
perature in  fever  either  by  increasing  the  resistance  of  the  regulat- 
ing center  to  the  disease  poisons,  or  by  lowering  the  degree  at 
which  the  heat-regulating  center  is  set  (if  we  may  use  such  an 
analogy) .  The  effect  of  these  drugs  is  not  to  any  extent  to  reduce 
heat-production,  for  they  do  not  diminish  metabolism,  and  ace- 
tanilid  even  increases  metabolism.  They  act  by  enabling  the  center 
to  improve  its  control  over  the  mechanisms  of  heat-dissipation, 
which  are  the  ones  at  fault  in  the  infectious  fevers. 

That  they  act  through  the  center  is  shown  by  their  failure  to 
affect  the  temperature  in  health,  by  their  failure  to  reduce  tem- 
perature if  the  spinal  cord  is  severed,  and  by  the  fact  that  there 
is  no  attempt  on  the  part  of  the  body,  as  the  temperature  falls, 
to  manufacture  more  heat  by  shivering,  etc.,  as  occurs  when  the 
temperature  is  reduced  by  external  cold  (cold  baths,  etc.).  The 
lowering  of  temperature  by  these  drugs  may  be  accompanied  by 
profuse  sweating,  but  this  is  a  result  of  the  action  upon  the  center, 
and  they  are  still  antipyretic  if  the  sweating  is  prevented  by 
atropine.  Occasionally,  as  the  result  of  their  action,  the  center 
reasserts  itself  too  strongly,  overshoots  the  mark,  and  carries  the 
temperature  away  below  the  normal.  In  some  cases  this  results  in 
collapse. 

Schutze  has  shown  that  antipyrine  does  not  prevent  the  forma- 
tion of  antitoxins  in  the  body,  so  it  does  not  interfere  with  the 
natural  forces  of  protection  against  disease,  except  as  fever  is 
beneficial. 

The  other  parts  of  the  nervous  system  are  also  affected  prac- 
tically alike  by  these  three  drugs. 

Cerebrum. — This  is  somewhat  depressed,  all  three  remedies 
being  useful  in  overcoming  nervous  irritability  and  restlessness. 
They  have  also  a  notable  power  in  lessening  pain,  especially  that 
from  neuralgia  or  neuritis,  or  a  lesion  of  the  central  nervous  system. 
They  are  especially  useful  in  headache.  Head  suggests  the  hy- 
pothesis that  the  analgesia  is  the  result  of  an  action  on  synapses  in 
the  pain-conveying  tract  in  the  thalamus  adjacent  to  the  heat- 
center.  Stekel  believes  that  the  action  in  headache  is  due  to  the 
regulation  of  the  balance  between  heat-production  and  heat-loss. 
In-  migrainal  headache,  for  example,  he  noted  that  there  was 
diminished  surface  temperature,  as  noted  in  the  axilla,  though 
normal  rectal  temperature,  and  that  after  small  doses  of  anti- 
pyrine the  axillary  temperature  rose  as  much  as  one  degree  with 
the  disappearance  of  the  headache. 

These  remedies  are  not  strongly  hypnotic,  and  do  not  pro- 
duce somnolence  if  the  patient  is  up  and  about;  yet  if  taken  at 
bedtime,  they  favor  the  onset  and  maintenance  of  normal  sleep. 


Fig.  53. — Acetanilid,  0.4  mg.  per  kilo.  Ventricle  (upper  tracing)  shows  increased 
tonicity  and  diminished  contractility  (down-stroke,  systole).  Arterial  pressure, 
lower  tracing,  falls  from  75  to  42  mm.  The  pulse-rate  drops  from  130  to  120. 
(Tracing  made  by  Dr.  C.  C.  Lieb.) 


Fig.  55. — Urticarial  eruption  following  antipyrine  (W.  S,  Gotthei]  in  Archives  of 

I  diagnosis  1. 


Fig.  56. — Exfoliative  dermatitis  following  the  administration  of   large  doses  of 
antipyrine.     Hair  and  nails  shed  (Scharnberg). 


THE    ANALGESIC   ANTIPYRETICS  44 1 

The  cerebral  cortex,  then,  is  partly  depressed ;  yet  even  large  doses 
seem  to  have  very  little  depressing  effect  on  the  intellectual 
functions.  This  distinguishes  them  markedly  from  morphine, 
the  bromides,  and  other  central  depressants.  Phenacetin,  being 
an  ethyl  compound,  is  more  hypnotic  than  the  others;  antipyrine 
is  the  least  hypnotic.  But  antipyrine  is  said  to  be  more  depress- 
ing to  the  motor  areas,  so  that  it  has  been  used  in  epilepsy, 
chorea,  and  whooping-cough  with  more  or  less  benefit. 

The  centers  of  the  medulla  are  scarcely,  if  at  all,  affected.  In 
poisoning,  convulsions  may  occur,  due  probably  to  stimulation 
of  the  spinal  cord  centers,  or  perhaps  to  asphyxia. 

Circulation. — A  number  of  cases  of  collapse  following  the  use 
of  antipyrine,  phenacetin,  and  acetanilid  have  been  reported,  so 
these  drugs  have  acquired  a  bad  reputation  as  circulatory  depress- 
ants. In  experimental  work  the  heart  muscle  is  directly  stimu- 
lated by  ordinary  doses,  the  beat  being  stronger  and  more  rapid. 
But  from  large  closes  the  muscle  is  weakened,  and  the  beat  may 
be  slow  and  irregular,  causing  collapse. 

Acetanilid,   

. .  ■■■■■■■Hm 


Acetanilid.  fl^HHH^^^^^^^^^^^^BHHHMi^HHH 

Acetanilid, 

caffeine,         ^^ 

■RHHBHHHHMOHMHIMBI^BMBMHH 

Acetanilid,    _^^^^^^^^^^^_^^^^^^^^^^^^^^__^^^^^^^^_^^^^^^^^^^^^^ 

caffeine  .  .  .   B| 

Fig.  54. — Toxicity  of  acetanilid  increased  strikingly  by  caffeine,  decreased  by 
sodium  bicarbonate.  Experiments  on  mice  by  Worth  Hale.  The  degree  of 
toxicity  is  represented  by  the  length  of  the  bars. 

The  collapse  action  is  most  pronounced  with  acetanilid,  and 
when  it  occurs  from  moderate  doses,  would  seem  to  be  due  to 
idiosyncrasy.  Nearly  all  the  fatalities  or  cases  of  serious  collapse 
from  these  drugs  have  come  from  very  large  doses  taken  in  the 
form  of  proprietary  headache  and  anti-pain  remedies.  Many  of 
these  cases  have  occurred  from  preparations  containing  caffeine, 
which  is  often  added  as  a  heart  stimulant,  and  it  has  been  shown 
by  Worth  Hale  that  they  are  more  dangerous  with  caffeine  than 
without,  and  less  dangerous  with  sodium  bicarbonate. 

Employed  in  proper  dosage,  these  drugs  are  practically  as  safe 
as  any  other  powerful  depressants,  but  must  be  used  with  equal 
caution.  The  skin  vessels  are  dilated  in  fever,  apparently  as  a 
result  of  the  action  of  the  heat-regulating  center. 

Metabolism. — Antipyrine  and  phenacetin  have  probably  no 
appreciable  effect  on  the  metabolism  in  health,  as  shown  by  the 
elimination  of  N,  the  absorption  of  02,  and  the  elimination  of 
C02.  Acetanilid  increases  metabolism,  as  shown  by  an  increase 
in  the  urea  and  total  nitrogen  of  the  urine. 


442  PHARMACOLOGY  AND  THERAPEUTICS 

In  fever,  in  association  with  the  reduction  of  the  temperature, 
the  metabolism  is  lessened. 

Excretion  is  by  the  kidneys.  Antipyrine  appears  in  the  urine 
either  unchanged  or  as  oxyantipyrine  in  combination  with  glycu- 
ronic  and  sulphuric  acids.  Acetanilid  appears  as  para-amidophe- 
nol.    Phenacetin  appears  as  phenetidin  compounds. 

Untoward  Effects. — From  idiosyncrasy,  antipyrine  not  infre- 
quently has  produced  a  scarlatiniform  rash  with  edema  of  the 
face  and  fever;  or  urticaria,  or  a  vesicular,  bullous,  or  eczematous 
eruption.  The  chief  untoward  effects  from  acetanilid  and  phe- 
nacetin are  cyanosis  and  collapse ;  a  petechial  eruption  has  been 
noted  from  phenacetin. 

Toxicology. — Acute  poisoning  shows  in  affections  of  the  alimen- 
tary tract  and  nervous  system.  There  are:  burning  and  swelling 
of  the  whole  alimentary  tract,  with  stomatitis,  nausea,  vomiting, 
gastritis,  perhaps  enteritis,  mental  dulness,  tremors,  convulsions 
(cerebral) ,  and  coma.  Death  results  from  failure  of  the  respira- 
tion. With  acetanilid  and  phenacetin  cyanosis  and  collapse  may 
occur  early.  Toxic  effects  in  a  girl  of  twenty  have  been  reported 
from  10  grains  of  antipyrine.  The  treatment  is  by  demulcents 
for  the  gastro-intestinal  tract,  and,  if  necessary,  measures  to  com- 
bat collapse. 

Chronic  Poisoning. — Many  nervous  patients  have  the  habit  of 
taking  these  drugs.  The  habit  does  not  have  a  hold  upon  them, 
like  the  morphine  habit,  and  can  be  broken  without  any  systemic 
rebellion;  yet  it  is  a  difficult  habit  to  overcome,  for  the  symptoms 
are  never  startling,  and  the  friends,  not  perceiving  any  harm  from 
the  drug,  note  the  apparent  suffering  when  the  drug  is  stopped 
(headache,  irritability,  restlessness,  sleeplessness).  There  is  a 
proneness  to  digestive  disturbances,  to  neuroses,  to  neuralgic 
pains,  to  various  skin  rashes,  as  erythema  and  eczema,  or  simple 
itching  without  a  rash,  and  to  mild  forms  of  neuritis.  There  may 
be  dyspnea  on  exertion,  and  other  evidences  of  cardiac  weakness. 
Impotence  has  been  reported. 

A  common  result  of  poisoning  by  acetanilid  and  phenacetin 
is  a  marked  cyanosis,  with  which  there  may  be  more  or  less 
dyspnea,  rapid  heart,  and  even  collapse.  There  is  some  destruc- 
tion of  red  cells,  and  some  formation  of  methemoglobin  by  reduc- 
tion, but  the  cyanosis  seems  to  be  out  of  proportion  to  the  methem- 
oglobin formation  and  out  of  proportion  to  the  patient's  symp- 
toms. There  is  probably  some  other  reduction  compound  present 
in  the  blood,  and  Bachmann  says  that  it  is  aniline. 

Ten  grains  of  acetanilid  taken  internally  have  produced 
cyanosis,  also  acetanilid  powder  applied  to  ulcer  of  the  leg.  The 
author  saw  one  case  from  a  phenacetin  powder,  probably  10 


THE   ANALGESIC   ANTIPYRETICS  443 

grains,  given  by  a  pharmacist  for  headache.  We  have  also  had 
under  our  care  one  striking  case  of  chronic  poisoning  with  cyano- 
sis which  persisted  for  weeks  after  the  stoppage  of  the  drug.  Many 
chemic  and  spectroscopic  tests  of  the  blood  revealed  no  foreign 
chemical  other  than  methemoglobin.  Antipyrine  does  not  have 
this  effect  upon  the  blood. 

Therapeutics. — Antipyrine,  in  10  to  25  per  cent,  solution,  is 
employed  locally  to  stop  nasal  hemorrhage,  and  as  an  application 
in  the  painful  throat  of  tuberculous  laryngitis.  Systemically,  it 
has  been  used  with  moderate  success  as  a  motor  depressant  and 
general  sedative  in  chorea  and  whooping-cough.  It  has  also  some 
employment  in  diabetes  insipidus  and  diabetes  mellitus.  Its  other 
uses  are  those  of  acetanilid  and  phenacetin.  Acetanilid  is  em- 
ployed slightly  as  an  antiseptic  dusting-powder. 

All  the  drugs  of  the  group  are  employed  very  largely  for  their 
effects  upon  the  nervous  system  and  in  fever.  Their  general 
therapeutic  powers  are : 

(a)  To  Overcome  Fever. — In  the  high  temperature  of  influenza, 
tonsillitis,  etc.,  these  drugs  act  not  merely  by  reducing  the  tem- 
perature, but  also  greatly  promote  the  comfort  of  the  patient  by 
lessening  pain,  if  present,  by  lessening  nervousness  and  headache, 
and  by  promoting  quiet  and  rest.  There  are  cases  of  typhoid 
fever  in  which  these  antipyretics  have  a  decidedly  better  effect 
than  the  cold  bath,  as  when  there  are  shivering  and  cyanosis  dur- 
ing the  bath  and  for  some  time  afterward,  and  discomfort  both 
physically  from  the  cold  and  mentally  from  the  dread  of  the  next 
bath.  The  drugs  are  much  used  where  cold  baths  are  not  prac- 
ticable, and  their  antipyretic  and  quieting  effects  usually  last 
from  four  to  eight  hours.  In  the  afternoon  fevers  of  tuberculosis, 
also,  they  promote  the  comfort  of  the  patient.  If  they  cause  too 
much  perspiration,  atropine  may  be  added. 

(b)  To  relieve  pain  in  conditions  without  fever,  as  in  dysmen- 
orrhea and  muscular  rheumatism;  headache,  migraine,  neuralgia, 
sciatica,  peripheral  neuritis;  the  lightning  pains  of  locomotor 
ataxia,  and  the  pain  of  an  intracranial  or  spinal  tumor. 

(c)  To  allay  nervous  excitability  and  promote  sleep  in  conditions 
without  fever — emotional  shock,  hysteria,  and  nervous  conditions 
in  general. 

Administration. — Usually  in  capsules  or  tablets.  If  they  cause 
too  much  sweating,  add  atropine;  if  too  much  depression,  add 
strychnine. 


444  PHARMACOLOGY  AND  THERAPEUTICS 

The  Anti-malarial  Antipyretics 
cinchona 

There  are  two  medicinal  varieties  of  cinchona,  one  the  bark 
of  several  species  of  calisaya,  and  known  officially  as  Cinchona, 
the  other  the  bark  of  the  red  cinchona,  known  as  "Peruvian  bark," 
and  with  the  official  title.  Cinchona  rubra.  These  are  natives  of 
South  America,  but  many  species  are  cultivated  in  various  tropi- 
cal countries. 

Constituents. — There  are  about  19  alkaloids,  the  important 
ones  being  quinine,  cinchonine,  quinidine,  and  cinchonidine.  In 
addition  there  are  quinic,  quinovic,  and  tannic  acids.  Red  bark 
contains  more  tannic  acid  and  less  quinine  than  calisaya,  but  both 
are  required  to  contain  5  per  cent,  of  total  alkaloid.  The  United 
States  Pharmacopoeia  specifies  that  calisaya  shall  contain  not  less 
than  4  per  cent,  of  ether-soluble  alkaloid,  i.  e.,  quinine,  cinchonine, 
and  cinchonidine. 

Preparations  and  Doses. — Fluidextract  (calisaya);  dose,  15 
minims  (1  c.c).  Tincture,  20  per  cent,  (calisaya) ;  dose,  30  minims 
(2  c.c).  Compound  tincture  (tinctura  cinchonae  composita),  10 
per  cent,  red  bark  with  serpentaria  and  bitter  orange  peel;  dose, 
1  dram  (4  c.c). 

The  alkaloidal  salts,  dose,  5  grains  (0.3  gm.),  are: 

Quinine  sulphate,  ^oH^^C^-H^SOi,  soluble  in  720  parts  of 
water  and  86  of  alcohol.  It  is  readily  soluble  in  dilute  hydro- 
chloric, sulphuric,  orphosphoric  acids,  as  it  forms  the  soluble  double 
salts,  or  in  the  case  of  sulphuric  acid,  the  soluble  bisulphate. 
Quinine  bisulphate,  C2oH24N202.H2S04,  soluble  in  8.5  parts  of 
water  and  18  of  alcohol.  Quinine  bromide,  soluble  in  40  parts  of 
water  and  0.67  of  alcohol.  Quinine  chloride,  soluble  in  18  parts 
of  water  and  0.6  of  alcohol.  Quinine  salicylate,  soluble  in  77  parts 
of  water  and  11  of  alcohol.  Cinchonine  sulphate,  soluble  in  58 
parts  of  water  and  72  of  alcohol. 

A  much  used  preparation  is  the  double  chloride  of  quinine  and 
urea,  better  known  as  the  bimuriate  of  quinine  and  urea.  It  is 
soluble  in  its  own  weight  of  water,  and  is,  therefore,  suitable  for 
hypodermatic  administration.  It  is,  moreover,  non-irritating. 
Its  solutions  are  unstable. 

Euquinine,  not  official,  is  the  ethyl  carbonic  ester.  It  is 
insoluble  in  water  and  not  bitter.  Its  dose  is  twice  that  of  the 
official  quinine  salts. 

Tinctura  anti periodica,  N.  F.  (Warburg's  tincture),  is  a  bitter, 
aromatic,  laxative,  sedative  and  antimalarial  "shot-gun"  pre- 
scription. It  is  made  of  quinine  sulphate,  aloes,  rhubarb,  angel- 
ica  seed,  elecampane,  saffron,  fennel,  prepared  chalk,  gentian, 


CINCHONA 


445 


zedoary,  cubeb,  myrrh,  camphor,  white  agaric,  opium,  black 
pepper,  cinnamon,  ginger,  alcohol,  and  water.  Each  ounce  con- 
tains opium,  yi  grain  (0.008  gm.) ;  quinine  sulphate,  10  grains  (0.6 
gm.),  and  extract  of  aloes,  8  grains  (0.5  gm.).  The  dose  is 
1  dram  (4  c.c).  Warburg's  tincture  without  aloes  (sine  aloe)  is  the 
same  with  the  omission  of  the  aloes. 

Pilula  anti periodica,  N.  F.,  and  Pilula  antiperiodica  sine  aloe, 
N.  F.,  represent  1  dram  (4  c.c.)  of  the  corresponding  tinctures. 
A  mass  for  use  in  capsules  is  also  employed,  4  grains  (0.25  gm.) 
of  it  representing  1  dram  (4  c.c.)  of  the  tincture. 

Pharmacologic  Action. — Quinine  is  a  protoplasm  poison. 

Microorganisms. — Quinine  is  mildly  antiseptic,  and  retards 
the  development  of  bacteria  and  yeasts.  In  very  dilute  solution 
(1 :  10,000)  its  first  tendency  is  to  stimulate  or  irritate  protoplasm; 
but  the  stimulation  is  soon  followed  by  depression,  and  in  motile 
organisms,  especially  protozoa  (ameba,  Paramecium)  and  ciliated 
cells,  all  motion  very  soon  ceases.  Strong  solutions  cause  instan- 
taneous cessation  of  movement  and  kill  the  organisms.  The 
spirochetes  of  relapsing  fever  are  more  resistant,  and  can  live  in 
a  solution  of  1 :  500. 

It  is  an  interesting  fact  that  various  cells,  under  the  influence 
of  quinine,  will  undergo  asymmetric  cell  division,  e.  g.,  the  ova. 
In  certain  low  vertebrates,  as  the  salamander,  dilute  solutions  of 
quinine  applied  to  the  epithelium  will  produce  cells  of  atypical 
mitosis  like  those  of  cancer.  This  effect  is  produced  by  other  pro- 
toplasmic poisons,  such  as  chloral  and  cocaine  (Wilson). 

The  enzymes  seem  to  be  slightly  retarded,  but  are  not  nearly 
so  much  affected  as  the  living  organisms.  Of  the  digestive  fer- 
ments, ptyalin  and  diastase  are  little,  if  any,  affected,  and  pepsin 
and  trypsin  are  distinctly  retarded  in  their  activity.  Other  fer- 
ments, such  as  the  blood-coagulating  and  the  oxidizing,  are  re- 
tarded ;  and  it  is  said  that  quinine  will  prevent  blood  or  fresh  vege- 
tables from  giving  the  guaiac  test,  which  depends  on  oxidation. 

The  leukocytes,  which  resemble  amebae  so  closely,  are  affected 
in  the  same  way  as  amebae.  With  1  part  of  quinine  in  4000  of 
blood  they  lose  their  ameboid  movements,  become  spheric,  die, 
and  soon  disintegrate.  In  the  intact  animal,  a  strong  solution 
prevents  the  emigration  of  leukocytes  and  their  gathering  to 
form  pus  at  the  site  of  inflammation.  And  while,  in  man,  such 
doses  as  can  be  administered  do  not  show  this  pronounced  effect, 
still  there  is  some  effect  upon  the  leukocytes,  for  their  number 
may  be  reduced  to  one-half  or  one-fourth  the  normal  (2000  to  4000 
per  c.mm.  instead  of  8000),  the  polynuclears  being  reduced  out 
of  proportion  to  the  lymphocytes.  Roth  (1913)  found  a  primary 
slight  increase  in  the  lymphocytes,  which  after  several  hours 


446  PHARMACOLOGY  AND   THERAPEUTICS 

changed  to  a  decrease.  In  a  dog  an  intravenous  dose  markedly 
contracted  the  spleen  and  caused  a  decided  decrease  in  the  white 
cells,  especially  of  the  polynuclears.  He  thought  the  primary 
rise  in  man  might  be  due  to  squeezing  out  the  splenic  leukocytes 
by  its  contraction.     These  are  notably  of  the  lymphocyte  type. 

Locally,  the  inorganic  salts  are  distinctly  irritant  to  raw  sur- 
faces and  mucous  membranes,  as  when  its  solutions  are  used  in 
the  rectum  or  hypodermatically.  After  a  hypodermatic  of  the 
chloride  of  quinine  and  urea  there  soon  ensues  a  pronounced  local 
anesthesia  which  lasts  for  some  hours.  Quinine  is  said  to  stimu- 
late the  growth  of  hair,  and  is  an  ingredient  of  rum  and  quinine, 
eau  de  quinine,  and  other  mixtures  which  are  sold  as  hair-stimu- 
lants. 

Alimentary  Tract. — It  is  intensely  bitter,  and,  given  before 
meals,  acts  as  a  bitter  to  promote  appetite.  Large  doses  irritate 
the  stomach  and  may  cause  nausea  and  even  vomiting.  There  is 
slight  retardation  in  the  activity  of  pepsin  and  trypsin,  while  the 
other  digestive  ferments  are  probably  not  affected.  It  is  to  be 
borne  in  mind  that  quinine  sulphate,  the  alkaloidal  salt  almost 
universally  employed,  requires  an  acid  medium  for  its  solution; 
therefore  it  is  administered  after  meals. 

Quinine  is  said  to  retard  the  absorption  of  salts,  and  also 
probably  of  other  substances  (foods  and  medicines),  from  the 
stomach  (Sollmann). 

Absorption. — If  the  quinine  salt  goes  into  solution  it  is  rapidly 
absorbed  from  the  stomach  and  may  appear  in  the  urine  in  fifteen 
minutes.  If  the  stomach  is  not  acid,  the  quinine  may  not  dis- 
solve. 

Circulation. — In  ordinary  therapeutic  doses  there  is  probably 
a  slight  increase  in  the  rate  of  the  heart  and  a  tendency  to  a  rise 
in  the  blood-pressure  from  mild  stimulation  of  the  heart  muscle 
and  of  the  arterial  muscles.  The  arterial  action  is  a  peripheral 
one,  for  on  perfusing  an  isolated  viscus,  there  is  contraction  of 
the  arterioles,  followed  in  a  short  time  by  their  dilatation.  In 
large  doses  there  is  direct  depression  of  the  muscles  of  the  heart 
and  of  the  arteries,  with  slow  pulse  (which  occurs  after  atropine, 
so  is  due  to  muscular  depression),  and  a  fall  in  blood-pressure. 
From  ordinary  therapeutic  doses  the  effect  on  the  circulation  is 
negligible. 

The  blood  we  have  already  spoken  of.  Its  coagulability  is 
decreased  and  its  white  cells  are  lessened  in  number  and  probably 
also  in  activity.  In  bleeding  experiments  on  dogs,  de  Sandro 
(191 1)  noted  that  dogs  given  quinine  recovered  their  hemoglobin 
and  red  cells  less  readily  than  those  without  quinine. 

Cerebrum. — It  has  the  same  tendency  as  the  other  antipy- 


CINCHONA  447 

retics,  but  not  to  so  great  a  degree,  to  allay  the  pains  of  neural- 
gia and  those  associated  with  the  onset  of  influenza  and  other 
acute  illnesses.  Large  doses  produce  cinchonism,  spoken  of 
later. 

Medulla. — Affected  only  in  poisoning.  Then,  after  a  brief 
stimulation,  the  respiratory  center  is  depressed,  and  death  takes 
place  from  its  paralysis. 

Spinal  Cord. — In  the  frog  the  reflexes  are  increased.  In 
mammals  there  is  probably  no  effect. 

Peripheral  Nerves. — After  hypodermatic  administration  there 
is  a  slow  and  prolonged  abolition  of  sensation  at  the  site  of 
injection. 

The  Eye. — In  some  persons  there  have  been  marked  changes 
in  the  sight  after  a  therapeutic  dose.  There  are  diminished  acute- 
ness  of  vision,  contraction  of  the  field  of  vision,  color-blindness, 
and  dilated  pupil. 

In  the  fundus  there  are  seen  contraction  of  the  retinal  arteries, 
with  anemia  of  the  retina  and  pallor  of  the  optic  discs,  thrombosis 
of  the  central  vein,  and  in  some  cases  atrophy  of  the  optic  nerve, 
with  more  or  less  permanent  blindness.  The  diminished  vision 
is  known  as  "quinine  amblyopia."  The  blindness  is  known  as 
"quinine  amaurosis."  DeSchweinitz  reports  a  case  of  temporary 
blindness  after  12  grains  of  quinine  sulphate,  though  usually  the 
doses  have  been  large.  According  to  this  author  the  contracted 
field  of  vision  does  not  regain  its  normal  limits;  but  Parker  (19 12) 
reported  the  case  of  a  man  who  took  240  grains  (15  gm.)  by  mis- 
take, was  completely  blind  for  a  time,  and  had  recovered  full 
vision  in  three  and  one-third  months. 

Ear. — The  deafness  and  ringing  in  the  ears  which  are  of  such 
frequent  occurrence  seem  to  be  due  mostly  to  congestion,  though 
anemia  is  reported  of  the  middle  ear  and  labyrinth.  Such  con- 
gestion has  been  found  in  animals  after  large  doses.  If  the  quinine 
administration  is  continued,  permanent  deafness  may  result  either 
from  degenerative  changes  in  the  spiral  ganglia  of  the  cochlea  or 
from  a  chronic  otitis  media  arising  from  the  continued  conges- 
tion. 

Muscle. — Striped  and  cardiac  muscles  are  stimulated  at  first, 
the  muscles  being  more  irritable  and  able  to  lift  a  greater  load; 
but  they  are  soon  fatigued,  and  their  total  work  amounts  to  less 
than  normal.  That  the  muscle  itself  is  the  part  affected  is  proved 
because  quinine  has  the  same  effect  after  curare.  (Curare  para- 
lyzes the  motor  nerve-endings  to  voluntary  muscle.)  Smooth 
muscle  is  not  so  surely  affected,  except  perhaps  the  spleen  and 
uterus,  and  perhaps  that  of  the  arteries. 

Elimination. — It  appears  very  soon  in  the  urine  (fifteen  to 


448  PHARMACOLOGY   AND   THERAPEUTICS 

thirty  minutes),  and  most  of  it  is  excreted  in  a  few  hours.  Traces 
may  be  detected  for  three  days  or  more.  From  30  to  90  per  cent, 
of  it  may  be  recovered  from  the  urine  unchanged,  and  some  is 
changed  to  di-hydroxyl  quinine.  A  small  amount  appears  in  other 
secretions.  Koldewijn  says  that  traces  appear  in  the  milk. 
Through  irritation  or  circulatory  changes  of  the  skin  there  may 
be  various  rashes,  notably  a  scarlatiniform  rash,  eczema,  urti- 
caria, and  erythema  with  itching.  So  frequent  are  skin  rashes 
from  quinine  that  a  rash  of  unusual  type  regularly  elicits  the 
physician's  question,  "Have  you  taken  quinine?" 

Kidneys. — Large  doses  of  quinine  irritate  the  kidneys  and 
cause  albuminuria  or  even  hemoglobinuria  or  hematuria. 

Uterus. — Uterine  contractions  seem  to  be  favored,  and  the 
drug  is  employed  in  labor  to  increase  the  force  of  the  contraction 
of  the  second  stage.  It  never  causes  a  tetanic  contraction  as  do 
ergot  and  pituitrin,  but  seems  simply  to  strengthen  the  usual 
intermittent  expulsive  contractions  which  take  place  at  this  time. 
It  is  a  common  belief  that  quinine  may  produce  abortion  in  a 
pregnant  woman,  and  I  have  seen  several  cases  where  abortion  in 
the  first  three  months  followed,  though  it  may  not  have  been 
caused  by,  its  use  for  cold  or  for  malaria.  There  are  also  many 
cases  of  pregnancy  where  abortion  has  not  followed  its  use. 

Metabolism  is  affected  by  very  small  doses,  even  doses  small 
enough  to  have  no  other  effect.  At  first  there  is  a  slight  increase 
in  the  nitrogenous  content  of  the  urine,  probably  due  to  increased 
leukocyte  destruction;  but  soon  there  is  a  marked  decrease,  and 
this  is  especially  noticeable  in  the  urea  and  uric  acid.  The  same 
amount  of  nitrogenous  food  may  be  absorbed,  but  less  is  consumed 
by  the  body,  so  there  is  a  storing-up  of  proteins.  Quinine  has, 
then,  just  the  opposite  effect  to  fever,  which  is  associated  with 
excessive  protein  destruction.  There  is  no  evidence  of  incomplete 
oxidation  of  the  nitrogenous  products. 

Temperature. — The  normal  oxidation  processes  are  changed 
very  little,  if  at  all,  the  02  taken  in,  and  the  C02  given  off,  being 
about  the  same.  Oxidation  is  usually  taken  as  a  criterion  of  the 
amount  of  heat  generated,  yet  there  is  less  heat  generated  by 
quinine,  presumably  owing  to  its  lessening  the  destruction  of 
proteins.  Quinine  lowers  the  temperature  in  fever  almost  entirely 
by  lessening  the  production  of  heat;  and  as  it  lowers  temperature 
after  division  of  the  spinal  cord,  it  does  not  exert  this  action 
through  the  heat-regulating  center. 

Like  all  antipyretics,  it  acts  best  at  about  the  time  of  a  usual 
remission  of  temperature,  and  has  but  little  effect  in  health.  It 
is  not  so  powerful  a  reducer  of  temperature  as  acetanilid,  and  in 
a  continuous  fever,  like  typhoid,  has  very  little  effect.     As  an 


Fig.  57. — Purpuric  and  vesicular  eruption  from  quinine  (W.  S.  Gottheil  in  Archives 

of  Diagnosis). 


CINCHONA  449 

antipyretic  it  has  largely  been  supplanted  by  more  effective 
drugs. 

Untoward  Symptoms. — Cinchonism,  skin  eruptions,  gastric 
disturbances,  diarrhea,  and,  rarely,  hemoglobinuria.  In  cincho- 
nism there  are  fulness  in  the  head  (headache) ,  ringing  in  the  ears, 
deafness,  dizziness,  and  mental  dulness;  and  there  may  be  im- 
paired vision,  muscular  weakness  with  uncertain  gait,  and  slow, 
rather  weak  pulse.  The  cerebral  symptoms  are  attributed  to 
circulatory  changes. 

In  some  people  there  is  idiosyncrasy  to  very  small  doses,  and 
in  these  susceptible  people  the  addition  of  bromides  lessens  the 
tendency  to  cinchonism. 

Poisonous  Symptoms. — The  usual  manifestation  of  overdosage 
is  cinchonism  (just  described).  Very  large  doses  induce  gastro- 
intestinal disturbances,  mental  sluggishness,  disturbance  of  sight 
and  hearing,  slow,  ineffective  respiration,  slow,  weak  heart, 
muscular  weakness,  and  collapse.  One  ounce  (30  grams)  produced 
only  confusion  and  noises  in  the  ears,  but  it  may  not  have  been 
absorbed.  Quill  reports  unconsciousness  and  severe  collapse  five 
minutes  after  the  taking  of  ]A  ounce  (15  gm.)  in  solution.  Baer- 
mann  reports  death  after  two  doses  of  8  grains  (0.5  gm.). 
Two  drams  (8  gm.)  have  also  been  reported  as  causing  death. 
Hartshorn  had  a  case  with  burning,  swollen  face,  scarlatiniform 
rash,  and  fever.  The  author  had  a  patient  in  whom  the  adminis- 
tration of  quinine  on  different  occasions  was  followed  by  chilli- 
ness, sweating,  vomiting,  and  diarrhea. 

The  treatment  is:  for  cinchonism,  bromides;  for  collapse,  the 
regular  treatment  for  collapse. 

Therapeutics. — Locally. — 1.  Quinine  and  urea  chloride  in  so- 
lution have  come  into  extensive  use  as  a  local  anesthetic.  Hertz  - 
ler,  Brewster,  and  Rogers  consider  it  suitable  in  all  operations 
which  can  ordinarily  be  done  under  cocaine.  They  use  0.25  per 
cent,  in  normal  saline,  and  have  determined  that  stronger  solu- 
tions retard  healing.  Many  operators  use  solutions  of  1  to  3  per 
cent,  strength.  To  lessen  shock,  Crile  uses  it  in  major  operations 
to  anesthetize  the  field  of  operation  in  advance  of  cutting,  and 
so  cut  off  all  afferent  impulses.  Quinine  bisulphate,  1 :  3000  to 
1 :  500,  has  also  been  used  as  a  local  anesthetic. 

2.  Both  of  these  salts  have  been  employed  as  antiseptics  in 
gonorrheal  urethritis  and  vaginitis. 

3.  In  amebic  colitis,  and  for  pin-worms,  a  solution  of  quinine 
bisulphate  1 :  2000  to  1 :  500,  or  quinine  and  urea  chloride,  0.5  per 
cent.,  may  be  employed  as  a  colon  irrigation. 

4.  The  quinine  salts  have  frequently  been  added  to  hair 
tonics. 

29 


450  PHARMACOLOGY   AND   THERAPEUTICS 

Alimentary  Tract. — Its  sole  value  is  as  a  bitter,  and  for  this 
the  preferred  preparation  is  the  compound  tincture  of  cinchona. 
It  is  not  a  true  tonic,  for  it  tends  to  inhibit  the  proteolytic  en- 
zymes, to  irritate  the  stomach,  and  to  retard  absorption,  and 
does  not  have  any  good  effect  on  muscle  at  all. 

Systemically . — It  is  employed  as  an  antipyretic  and  analgesic 
to  reduce  the  pains  of  influenza  and  the  discomfort  of  a  cold.  In 
neuralgia  and  headache  it  is  analgesic,  and  may  also  act  by  lessen- 
ing the  nitrogenous  waste  products  which  are  sometimes  the 
cause  of  headache.  It  is  not  a  very  powerful  antipyretic  or 
analgesic.  In  bacterial  injections,  e.  g.,  septicemia,  it  would  seem 
to  be  harmful  rather  than  helpful,  for  it  depresses  vitality  and 
checks  phagocytosis.  For  uterine  effect  it  is  employed  in  men- 
orrhagia  and  uterine  inertia.  Among  skin  diseases,  it  has  been 
recommended  internally  in  pemphigus,  exfoliative  dermatitis, 
and  pityriasis  rubra. 

In  black-water  fever,  Cardamitis  says  that  quinine  does  more 
harm  than  good.  He  cites  1347  cases  treated  by  quinine,  with 
24.42  per  cent,  of  deaths,  and  1134  treated  without  quinine,  with 
7.32  per  cent,  of  deaths. 

In  pneumonia,  Solis-Cohen  uses  15  grains  (1  gm.)  of  quinine 
and  urea  chloride  hypodermatically,  repeated  every  two  or  three 
hours  for  2,  3,  or  4  doses.  The  fever  disappears  by  lysis  instead 
of  by  crisis.  Before  acceptance,  this  requires  extensive  clinical 
testing. 

In  malaria  it  is  practically  specific.  In  tertian  or  quartan 
malaria,  about  two  or  three  hours  after  a  large  dose  of  quinine, 
the  parasites  in  the  red  cells  can  be  seen  to  have  lost  their  ameboid 
motions,  and  they  soon  become  granular  and  die.  The  quinine 
acts  most  strongly  on  the  forms  just  breaking  into  spores  and  on 
the  free-swimming  organisms;  and  as  these  are  present  in  the 
blood  about  the  time  of  the  chill,  the  quinine,  on  account  of  its 
rapid  absorption  and  rapid  excretion,  is  best  given  just  at  this 
time.  Fifteen  grains  (1  gm.)  may  be  administered  just  before, 
during,  or  after  the  chill,  and  it  should  be  followed  by  5  grains 
three  times  a  day  for  one  or  two  months.  In  malarial  regions 
quinine  is  taken  in  large  quantities  (1  dram)  as  a  prophylactic; 
it  is  rapidly  excreted.  There  is  much  evidence  to  show  that  it 
does  reduce  the  number  of  cases  in  a  malarial  community,  and 
does  not  seem  to  do  any  harm  to  the  takers.  In  pernicious  mala- 
ria the  bimuriate  of  quinine  and  urea  in  10  per  cent,  solution 
has  been  employed  up  to  100  grains  in  a  day,  but  recovery  from 
this  condition  is  rare  in  any  case.  Brewster  reports  the  intra- 
venous administration  in  pernicious  malaria  of  100  grains  in  six 
hours  without  untoward  effects. 


SALICYLIC  ACLD 


451 


Administration. — For  its  bitter  effect,  the  cinchona  prepara- 
tions are  employed,  diluted  with  water.  For  systemic  effect,  the 
quinine  salts  are  preferred. 

These  salts,  because  of  their  bitterness,  are  usually  given  in 
capsules\>r  coated  pills.  The  sulphate  is  the  one  in  common  use, 
and  its  absorption  is  more  sure  and  more  rapid  if  it  is  given  in 
solution  with  a  dilute  mineral  acid,  as  sulphuric,  hydrochloric, 
phosphoric,  or  aromatic  sulphuric.  The  chloride  and  bisulphate 
are  to  be  preferred,  as  they  are  soluble  without  the  addition  of 
acid.  For  hypodermatic  use  the  bimuriate  of  quinine  and  urea  is 
employed. 

For  children,  it  may  be  given  in  the  form  of  the  comparatively 
tasteless  (because  insoluble)  t annate,  made  into  tablets  with 
chocolate — the  so-called  "quinine  chocolates";  or  it  may  be 
mixed  with  fluidextract  of  licorice  (incompatible  with  acids),  or 
with  syrup  of  yerba  santa,  which  has  the  peculiar  property  of 
lessening  the  appreciation  of  bitter  taste.  As  it  takes  some  time 
for  the  action  on  the  taste-buds  to  develop,  the  yerba  santa  prob- 
ably lessens  the  bitterness  solely  by  forming  the  insoluble  tan- 
nate. 

Quinine  is  thought  to  act  better  in  malaria  if  given  with  some 
aromatic,  as  ginger  or  capsicum,  or  with  arsenic,  and  this  is  espe- 
cially the  case  in  the  estivo-autumnal  variety  and  in  chronic 
malaria. 

The  other  alkaloids,  quinidine,  cinchonine,  and  cinchonidine, 
act  in  malaria  like  quinine,  but  in  poisoning  cause  epileptiform 
convulsions.  They  have  no  advantages  over  quinine  and  are 
more  expensive. 

Antirheumatic  antipyretics 
salicylic  acid 

Salicylic  acid,  acidum  salicylicum,  CeELjOH^COOH,  is  chemic- 
ally orthosalicylic  acid,  and  is  an  organic  acid  which  exists  natur- 
ally in  combination  in  the  volatile  oils  of  birch  and  wintergreen. 
It  is  generally  prepared  synthetically  from  phenol.  This  synthetic 
salicylic  acid  has  been  found  contaminated  with  meta-  and  para- 
salicylic  acids  and  with  cresotinic  acid,  which  are  said  to  be  de- 
pressing to  the  circulation;  but  the  commercial  product  of  today 
is  fairly  pure,  and  the  reputed  superiority  of  salicylate  made  from 
the  natural  oils  is  not  substantiated  by  the  experimental  work 
of  Eggleston  and  others.  Engelhardt  found  phenol  present  in  a 
number  of  samples  of  both  the  artificial  and  the  natural  oil.  Sali- 
cylic acid  has  a  biting  taste,  and  is  soluble  in  308  parts  of  water 


452  PHARMACOLOGY   AND   THERAPEUTICS 

and  in  2  parts  of  alcohol.  The  salts  of  the  alkali  metals  are 
readily  soluble  in  water. 

Preparations  and  Doses. — 1.  Salicylic  acid;  dose,  7^  grains 
(0.5  gm.). 

2.  The  alkali  salts — sodium,  lithium,  and  strontium  salicyl- 
ates; dose,  15  grains  (1  gm.). 

The  salts  of  ammonium,  quinine,  bismuth,  and  physostigmine 
are  official,  but  in  the  available  dosage  do  not  give  a  salicylic 
action. 

Microorganisms. — In  a  solution  of  1 :  500  salicylic  acid  is  anti- 
septic, and  will  inhibit  or  retard  the  growth  of  bacteria,  yeasts, 
and  molds;  and  as  in  these  dilutions  it  is  not  corrosive  to  living 
tissue,  or  poisonous  to  human  beings,  except  in  large  amounts,  it 
is  safe  for  use  in  and  about  the  body.  But  because  it  is  not  readily 
soluble  in  water,  its  use  as  an  antiseptic  is  confined  largely  to  the 
preservation  of  foods,  the  treatment  of  parasitic  skin  diseases,  and 
the  preparation  of  a  mild  antiseptic  wash  known  as  "boro-sal." 
Leach  says  that  quantities  sufficient  to  preserve  milk  affect  the 
taste  of  the  milk.  It  belongs  to  the  phenol  group  of  antiseptics, 
but  does  not  possess  the  destructive  properties  and  the  penetrat- 
ing power  of  carbolic  acid,  and  it  retains  its  antiseptic  power  in 
fatty  and  alcoholic  preparations. 

The  alkaline  salicylates,  though  less  antiseptic  than  the  acid 
itself,  are  freely  soluble  in  water  and  are  used  in  the  preservation 
of  foods. 

Enzymes. — The  action  of  these  is  inhibited  or  retarded,  a  1  per 
cent,  solution  being  sufficient  to  stop  the  ptyalin  action  on  starch. 
Pepsin  is  somewhat  lessened  in  its  activity,  and  probably  also  the 
other  digestive  ferments.  Very  weak  solutions  seem  to  favor  fer- 
ment action. 

Local  Action. — Besides  its  antiseptic  action,  it  tends  to  stop 
local  sweating,  as  of  the  hands  or  feet;  to  soften  and  facilitate  the 
removal  of  accumulations  of  horny  epithelium,  as  of  corns  or 
warts,  without  causing  inflammatory  changes  in  the  healthy 
underlying  tissues;  and  in  chronic  skin  diseases,  such  as  eczema, 
to  promote  the  growth  of  healthy  skin.  It  is  irritant  to  mucous 
membranes. 

Methyl  salicylate  and  the  volatile  oils  of  wintergreen  and  birch 
are  counterirritants. 

Alimentary  Tract. — Its  taste  is  biting,  and  it  is  locally  irritant. 
Its  tendency  is  to  retard  gastric  fermentation  and  the  action  of 
the  digestive  ferments.  Whether  or  not  it  can  reduce  intestinal 
putrefaction  is  a  question,  for  while  Strasburger  claims  that  the 
number  of  bacteria  in  the  feces  is  distinctly  reduced,  other 


SALICYLIC  ACID 


453 


observers  have  been  unable  to  detect  any  diminution  in  the 
indican  of  the  urine.    (See  Salol.) 

By  large  quantities  the  production  of  bile  is  increased,  but  the 
use  of  the  drug  for  this  purpose  in  therapeutics  has  not  been 
shown  to  have  any  value. 

The  volatile  oil  salicylates  have  a  typical  carminative  action, 
and  in  moderate  dosage  are  well  borne;  the  other  salicylates  are 
irritant  and  very  frequently  produce  nausea  and  even  vomiting. 

Absorption  is  rapid  from  the  stomach  and  duodenum. 

Systemically,  it  resembles  acetanilid  in  its  analgesic  properties, 
but  is  much  milder.  It  increases  metabolism,  yet  is  antipyretic 
by  dilating  the  vessels  and  promoting  sweating,  and  so  increasing 
heat-loss.  Whether  there  is  an  effect  on  the  heat-regulating 
center  or  not  is  not  proved.  Mandel  found  that  salicylates  would 
prevent  a  rise  of  temperature  from  xanthine.  These  analgesic 
and  antipyretic  effects  are  so  much  more  pronounced  in  acute 
articular  rheumatism  than  in  other  diseases  that  salicylic  acid  is 
believed  to  exert  a  specific  action  upon  the  causative  factors  of 
the  lesions  in  this  condition.  It  has  been  stated  that  it  cannot  be 
detected  in  the  synovial  fluid  of  normal  joints,  but  is  found  in  the 
fluid  of  the  inflamed  joints  of  acute  articular  rheumatism.  But 
Giglio  found  it  in  the  synovial  fluid  of  many  joints;  and  Filippi 
and  Nesti  obtained  it  from  the  synovial  fluid  from  the  hip-joint  of 
dogs  one  hour  after  its  administration  by  mouth.  It  was  present 
for  from  twenty-eight  to  fifty-four  hours.  They  found  it  also  in 
the  joints  of  acute  articular  rheumatism,  but  only  in  the  merest 
traces  in  a  gonorrheal  joint.  Dixon  states  that  the  joint  pain  and 
stiffness  are  removed  by  the  injection  into  the  joint  of  a  salicylate. 
According  to  Falk  and  Tedesco  (1909),  it  appears  in  all  inflam- 
matory exudates ;  and  they  recommend  this  as  a  diagnostic  point 
in  sputum  examinations.  They  claim  that  the  sputum  of  tuber- 
culosis and  pneumonia,  being  an  exudate,  gives  the  salicylic  test, 
while  the  sputum  of  bronchitis  and  bronchiectasis,  being  a  secre- 
tion, does  not  give  the  test.  Bastedo  and  Johnson  were  unable 
to  distinguish  by  this  test. 

Except  for  the  dilatation  of  the  skin  arterioles,  which  is  pro- 
nounced, the  effect  upon  the  circulation  is  usually  negligible  in 
therapeutics.  The  tendency  of  moderate  doses  is  to  stimulate 
slightly  the  heart  muscle  and  the  vasoconstrictor  center;  that  of 
large  doses  is  to  depress  them.  In  the  blood  the  leukocytes  tend 
to  be  increased  in  number. 

Metabolism. — As  shown  by  the  rise  of  nitrogen  and  sulphur 
in  the  urine,  there  is  increased  protein  destruction.  Both  urea 
and  uric  acid  are  increased,  the  rise  in  the  latter  being  sometimes 
as  much  as  50  per  cent.     This  is  attributed  by  some  writers  to 


454  PHARMACOLOGY  AND  THERAPEUTICS 

the  increase  in  the  number  of  leukocytes,  but  von  Noorden  states 
that  "of  salicylic  acid  and  its  products,  one  can  say  positively 
that  they  favor  the  elimination  of  uric  acid  in  gouty  subjects." 

Excretion  is  by  the  kidneys,  chiefly  as  salicyluric  acid,  a 
glycocoll  compound  which  gives  a  violet-red  color  with  ferric 
chloride.  Traces  are  also  found  in  the  bile,  milk,  and  sweat.  The 
appearance  in  rheumatic  and  other  inflammatory  exudates  has 
been  referred  to  above. 

The  kidneys  may  be  irritated  by  large  quantities,  and  diuresis 
sometimes  results.  But  among  drugs  of  this  class  salicylic  acid 
is  a  comparatively  safe  one,  for  quite  frequently  ioo  or  200  grains 
a  day  of  sodium  salicylate  have  been  given  without  signs  of  kidney 
inflammation.  Von  Noorden,  however,  warns  against  possible 
kidney  effects  in  gout. 

Toxicology. — The  early  signs  of  overdosage  are:  nausea,  vom- 
iting, and  sometimes  diarrhea;  or  headache,  ringing  in  the  ears, 
and  deafness;  or  mental  excitement.  As  judged  by  these  signs, 
Hanzlik  (1913)  found  that  for  human  adults  the  toxic  amount  of 
sodium  salicylate  is  about  200  grains  (i3gm.),of  methyl  salicylate 
and  aspirin  about  120  grains  (8  gm.),  and  of  diplosal,  100  grains 
(6.7  gm.). 

When  the  symptoms  resemble  those  of  cinchonism,  the  con- 
dition is  known  as  salicylism;  when  there  is  mental  excitation,  it 
is  known  as  salicylic  intoxication,  or  "salicylic  jag."  Salicylism 
is  characterized  by  fulness  in  the  head,  headache,  mental  dulness 
and  apathy,  with  ringing  in  the  ears,  deafness,  disordered  vision, 
and  muscular  weakness.  The  ear  symptoms  are  not  so  common 
as  from  quinine,  and  are  due  either  to  congestion  or  anemia  or  to 
degeneration  of  the  nerve-elements  of  the  cochlea.  Scheyer 
reports  a  case  of  labyrinthitis  with  permanent  impairment  of  the 
hearing.  The  eye  symptoms  are  also  associated  with  circulatory 
changes  in  the  retina  or  degenerative  changes  in  retina  or  optic 
nerve. 

In  the  salicylic  intoxication  the  cerebral  symptoms  resemble 
those  from  atropine.  The  patient  is  talkative  and  very  cheerful, 
and  may  pass  on  to  delirium  with  hallucinations,  motor  activity, 
and  attempts  to  get  out  of  bed. 

Very  large  doses  produce  weakness  of  the  heart  and  depression 
of  the  respiratory  and  vasoconstrictor  centers,  with  collapse.  But 
the  writer  has  frequently  seen  20  grains  of  the  sodium  salicylate 
given  every  two  hours,  and  occasionally  30  grains,  without  any 
noticeable  effect  on  the  heart's  action  or  the  blood-pressure. 
Hanzlik  found  no  especial  tolerance  for  the  salicylates  in  acute 
rheumatism.     (Although  phenol  and  salicylic  acid  are  closely 


SALICYLIC  ALLIES  455 

related  chemically,  nevertheless  they  cannot  be  considered  to- 
gether pharmacologically  or  therapeutically.) 

Therapeutics. — Locally,  salicylic  acid  itself  is  employed: 

1.  As  a  surgical  antiseptic,  in  the  form  of  Thiersch's  solution 
or  boro-sal  (acid  salicylic,  2;  acid  boric,  8;  in  water,  1000). 

2.  In  sweating  of  feet  and  hands,  in  alcoholic  solution;  and  in 
bromidrosis  (smelly  feet),  mixed  with  boric  acid,  and  placed  dry 
in  the  shoes. 

3.  In  fungous  skin  diseases  (ringworm,  etc.)  and  chronic 
eczema,  in  ointment  form.  Lassar's  paste  is  composed  of  salicylic 
acid,  15  grains  (1  gm.),  zinc  oxide  and  starch,  of  each,  2  drams 
(8  gm.),  and  petrolatum,  a  sufficient  quantity  to  make  1  ounce 
(30  gm.). 

4.  To  remove  corns  and  warts,  in  solution  in  flexible  collodion, 
15  grains  (1  gm.)  to  2  drams  (8  c.c).  It  should  not  be  applied 
beyond  the  corn,  or  it  may  cause  the  adjacent  skin  to  peel. 

Internally,  the  sodium  salicylate  is  regularly  employed: 

1.  In  acute  articular  rheumatism  and  its  complications — 10  to 
20  grains  (0.7-1.3  gm.)  every  two  or  three  hours. 

2.  In  acute  tonsillitis,  pharyngitis,  chorea,  growing  pains, 
sciatica,  lumbago,  muscular  rheumatism,  pleurisy,  etc.,  all  of  which 
may  have  a  true  rheumatic  origin.  Many  writers  speak  of  its 
uselessness  in  many  cases  of  chorea. 

3.  In  the  indefinite  muscular,  joint,  or  neuritic  pains,  which  are 
loosely  spoken  of  as  rheumatic. 

4.  In  gouty  attacks  it  may  have  value  for  a  short  time  (von 
Noorden).  In  chronic  gout  and  chronic  rheumatism  it  is  of  no 
value  at  all. 

5.  In  diabetes,  von  Noorden  (1912)  considers  it  the  most 
valuable  of  the  drugs  used,  except  the  nerve  sedatives  (codeine, 
etc.). 

Administration. — Sodium  salicylate  is  given  in  capsules  or 
cachets  with  plenty  of  water,  or  in  solution  in  wintergreen  water 
or  other  flavored  liquid.  Its  sweetish  taste  is  unpleasant  and 
nauseating  to  many.  The  addition  of  an  alkaline  bromide  lessens 
the  tendency  to  salicylism. 

Seibert  (191 1)  has  suggested  the  hypodermatic  use,  recom- 
mending the  injection  of  10  c.c.  of  a  20  per  cent,  solution  for  each 
100  pounds  of  body  weight.  He  repeats  the  dose  every  twelve 
hours,  preceding  it  by  an  injection  of  a  weak  cocaine  solution 
because  of  the  pain. 

SALICYLIC  ALLIES 
Acetyl-salicylic  acid,  or  aspirin,   C6H4.0.COCH3.COOH,  of 
slightly  sour  taste  and  acid  reaction,  is  soluble  in  125  parts  of 


456  PHARMACOLOGY  AND  THERAPEUTICS 

water  and  freely  in  alcohol.  It  gives  no  reaction  with  ferric 
chloride,  unless  previously  decomposed  by  alkalies  or  boiling 
with  water.  On  boiling  with  10  per  cent,  sodium  hydroxide 
solution  it  separates  into  its  components.  The  claim  is  made  that 
it  passes  through  the  stomach  unchanged,  and  is  decomposed  in 
the  alkaline  intestinal  contents  to  form  sodium  salicylate  and 
sodium  acetate;  but  sodium  carbonate  in  a  test-tube  does  not  so 
decompose  it.  Theoretically,  it  should  not  be  given  with  sodium 
bicarbonate  or  other  alkali,  lest  it  be  decomposed  in  the  stomach; 
but  in  the  author's  experience  the  bicarbonate  lessens  the  nausea 
and  heartburn  which  sometimes  result  from  the  drug. 

In  many  instances  it  has  proved  less  irritant  to  the  stomach 
than  either  salicylic  acid  or  sodium  salicylate,  but  not  infre- 
quently it  causes  hyperacidity  with  heartburn,  or  nausea  or 
vomiting. 

Aspirin  has  greatly  replaced  quinine  in  the  affections  of  the 
profession  and  the  laity,  and  is  prescribed  or  taken  in  5-grain 
(0.3  gm.)  tablets  or  capsules  every  two  or  three  hours  for  colds, 
sore  throat,  neuralgia,  headache,  and  influenza.  It  is  also  used 
wherever  a  salicylate  is  indicated.  Williamson  (1902)  found  that 
it  reduced  the  sugar  in  the  urine  in  a  number  of  cases  of  diabetes, 
but  not  in  the  severe  cases.    It  is  strongly  diaphoretic. 

Toxicology. — There  are  a  number  of  reports  of  angioneurotic 
swelling  of  the  face  and  throat,  or  general  urticaria,  with  or  with- 
out nausea,  vomiting,  dizziness,  and  collapse.  These  are  due  to 
idiosyncrasy,  and  have  usually  followed  small  doses,  such  as  15 
grains  (1  gm.).  Von  Xoorden  (1912)  says  that  in  three  of  his 
cases  acute  nephritis  followed  the  use  of  aspirin. 

Novaspirin  is  the  methyl-citric-acid  ester  of  salicylic  acid; 
diplosal  is  the  salicylic-acid  ester  of  salicylic  acid;  and  diaspirin 
is  succinyl  disalicylic  acid.  It  is  claimed  for  all  these  that  they 
pass  through  the  stomach  unchanged. 

Salol,  or  phenyl  salicylate,  C6H4.0H.COOC6H5,  is  in  the  form 
of  crystals  with  a  characteristic  aromatic  odor.  It  gives  a  violet 
color  with  ferric  chloride.  It  is  soluble  in  alcohol,  but  is  insoluble 
in  water  and  practically  insoluble  in  the  gastric  juice.  In  a  test- 
tube  alkalies  produce  the  odor  of  phenol,  and  in  the  alkaline  con- 
tents of  the  intestine  it  is  decomposed  and  goes  into  solution  as 
sodium  salicylate  and  phenol.  These  products  are  rapidly  ab- 
sorbed and  are  excreted  in  the  urine  as  salicyluric  acid  and  phenol 
sulphonates.  Whether  or  not  they  have  an  antiseptic  effect  in 
the  intestine  is  a  moot  question,  most  observers,  with  the  excep- 
tion of  Herter,  perhaps,  having  failed  to  note  a  diminution  of  the 
indican,  or  any  other  indication  of  diminished  putrefaction. 
Indeed,  phenol  itself,  judging  from  the  work  of  Richards  and 


COLCHICUM 


457 


Howland,  is  more  prone  to  increase  than  to  lessen  the  symptoms 
of  auto-intoxication.  Salol  is  sometimes  carried  through  the  intes- 
tines without  change,  the  odor  being  recognized  in  the  feces. 

In  its  customary  dose  of  5  grains  every  three  or  four  hours 
salol  can  have  but  little  salicylic  effect,  and  it  is  really  a  phenol 
drug  rather  than  a  salicylate.  It  is  antipyretic  and  analgesic, 
however,  and  is  frequently  given  with  phenacetin  for  colds  or 
influenza.  In  chronic  colitis  it  is  given  in  capsules  with  a  few 
minims  of  castor  oil.  In  diabetes,  Teschemacher  (1901)  noted  a 
decided  lessening  of  the  sugar  in  6  out  of  9  cases.  He  gave  15 
grains  (1  gm.)  four  times  a  day. 

As  shown  in  experimental  infections,  the  products  in  their 
excretion  tend  to  render  the  urine  antiseptic ;  hence  it  is  employed 
in  infections  of  the  urinary  tract. 

Salophen  is  salicylic-acetanilid.    Dose,  15  grains  (1  gm.). 

Saliphen  is  salicyl-paraphenetidin. 

Malakin  is  salicyliden-para-phenetidin. 

Mesotan  is  me  thy  1-oxy methyl  ester  of  salicylic  acid,  with  the 
properties  of  a  volatile  oil.  It  is  more  irritant  than  methyl  salicyl- 
ate, so  is  used  diluted  with  an  equal  quantity  of  olive  oil. 

Spirosal  is  monoglycol  ester  of  salicylic  acid,  has  also  the  prop- 
erties of  a  volatile  oil,  and  is  used  in  alcoholic  or  oily  solution. 

Salicin  is  a  glucoside  obtained  from  willow  and  poplar  barks. 
It  is  bitter  and  is  not  nauseating.  In  either  the  stomach  or  the 
duodenum  it  splits  up  to  form  salicyl  alcohol  and  other  close 
relatives  of  salicylic  acid.  (See  Glucosides,  Part  I.)  Its  use  is 
confined  to  the  milder  rheumatic  manifestations,  or  to  conditions 
of  the  stomach  which  prevent  ordinary  salicylic  medication. 
Dose,  20  grains  (1.3  gm.). 

Administration. — The  volatile  oil  types  of  salicylate  are  applied 
locally  over  the  inflamed  parts  either  by  rubbing  or  on  a  compress. 
Internally  they  are  given  in  capsules.  Aspirin,  salicin,  salol,  etc., 
are  best  given  in  capsules,  but  may  be  employed  in  tablet  form. 

Melubrin,  an  antipyrine  derivative,  is  not  a  salicylic  acid 
drug.  In  doses  of  1%  to  2  drams  (6-8  gm.),  in  a  period  of  six 
hours,  followed  by  15  grains  (1  gm.)  every  three  hours,  it  is  re- 
ported to  be  excellent  in  acute  articular  rheumatism.  It  is  a  new 
drug,  and  requires  extensive  clinical  testing. 

COLCHICUM 
Though  it  bears  no  relation  to  salicylic  acid,  colchicum, 
because  of  its  use  in  gout,  may  properly  be  mentioned  here.  Both 
the  seed  and  the  corm  of  Colchicum  autiimnalc  (fam.  Liliacece), 
a  crocus-like  plant,  are  official,  the  seed  being  required  by  the 
United  States  Pharmacopoeia  to  contain  not  less  than  0.55  per 


458  PHARMACOLOGY  AND  THERAPEUTICS 

cent,  of  the  alkaloid  colchicine,  and  the  corm  not  less  than  0.35 
per  cent. 

Preparations  and  Doses. — 

(a)  Colchicum  seed,  dose,  3  grains  (0.2  gm.). 

Fluidextract,  dose,  3  minims  (0.2  c.c). 
Tincture,  10  per  cent.,  dose,  30  minims  (2  c.c). 
Wine,  10  per  cent.,  dose,  30  minims  (2  c.c). 

(b)  Colchicum  corm,  dose,  4  grains  (0.25  gm.). 

Extract,  dose,  1  grain  (0.06  gm.). 

(c)  Colchicine,  dose,  tto  grain  (0.0005  gm.). 
Pharmacology. — Colchicum  is  a  gastro-intestinal  irritant,  the 

larger  therapeutic  doses  sometimes  causing  nausea,  vomiting,  and 
diarrhea.  In  poisoning  there  is  intense  gastro-intestinal  irritation, 
with  vomiting,  pain,  and  bloody  stools;  and  there  are  irritation  of 
the  kidneys  (a  remote  local  effect),  collapse,  and,  sometimes,  an 
ascending  paralysis,  beginning  in  the  legs.  Death  takes  place  from 
paralysis  of  respiration.  It  has  resulted  from  2V  grain  (0.003  Sm-) 
of  colchicine  in  a  case  of  gout  with  nephritis. 

There  are  no  constant  effects  upon  the  uric-acid  excretion  in 
gout  or  in  health,  and  there  is  nothing  in  the  pharmacology  of 
colchicum  that  explains  its  use  in  gout.  Yet  it  seems  to  have 
great  power  in  the  acute  attack  to  relieve  the  pain  and  swelling 
of  the  joints  and  to  shorten  the  attack.  In  the  words  of  von 
Noorden,  ''Colchicum  accelerates  the  critical  outpouring  of  uric 
acid  that  accompanies  gouty  seizures,  but  is  inert  in  the  intervals 
between  the  attacks,  and  in  chronic  and  atypical  gout." 

Cimicifuga,  black  snakeroot,  is  a  bitter  rhizome  of  the  north- 
eastern United  States,  sometimes  employed  in  gout  and  rheuma- 
tism. The  dose  of  the  fluidextract  is  15  minims  (1  c.c);  of  the  20 
per  cent,  tincture,  1  dram  (4  c.c);  of  the  extract,  4  grains 
(0.25  gm.). 

Atophan,  phenyl-chinolin-carboxylic  acid,  insoluble  in  water, 
but  soluble  in  alkalies,  and  with  a  biting  taste,  is  a  remedy  for 
gout  and  the  uric-acid  diathesis.  Deutsch  (191 2)  found  that  it 
increased  the  excretion  of  uric  acid  30  to  300  per  cent,  without 
other  change  in  the  urine.  He  thought  it  best  with  sodium  bicar- 
bonate to  prevent  the  precipitation  of  free  uric  acid  in  the  urine. 
In  some  cases  there  were  abdominal  pain  and  regurgitation  of 
food,  or  diarrhea.  Weintraud  believes  that  it  acts  on  the  tubule 
cells  of  the  kidney,  to  increase  their  power  of  excreting  uric  acid. 
It  is  not  diuretic.  Dose,  15  grains  (1  gm.),  three  times  a  day. 
It  is  still  in  the  experimental  stage. 

Piperazine,  diethylene-diamine,  is  hygroscopic  and  very  sol- 
uble in  water.     It  is  alkaline,  forms  salts  with  acids,  and   is 


DISINFECTANTS   AND   ANTISEPTICS  459 

incompatible  with  alkaloidal  salts,  metallic  salts,  tannic  acid, 
acetanilid,  and  acet-phenetidin.  On  the  finding  that  its  salt  with 
uric  acid  was  readily  soluble,  this  drug  was  brought  forward  as  a 
remedy  in  gout  and  the  uric-acid  diathesis;  but  its  value  is  ques- 
tionable, for  in  the  urine  it  is  usually  found  in  combination  with 
the  mineral  acids  rather  than  with  uric  acid.  Starling  reports  it, 
however,  as  promoting  the  excretion  of  uric  acid  by  the  tubule 
cells,  as  shown  in  kidney  experiments. 


DISINFECTANTS   AND   ANTISEPTICS 

A  disinfectant  is  an  agent  that  has  the  power  to  destroy 
microbic  life,  i.  e.,  it  is  a  germicide.  An  antiseptic  is  an  agent  that 
tends  to  retard  the  growth  of  microorganisms. 

A  deodorant  or  deodorizer  is  an  agent  that  will  destroy  or  over- 
come a  foul  odor.  It  may  or  may  not  be  disinfectant.  Examples 
of  such  are:  (1)  For  general  use,  chlorinated  lime,  cologne  water, 
charcoal,  the  smoke  of  burning  paper,  burning  straw,  or  burn- 
ing coffee;  (2)  for  bad  breath,  antiseptic  solution,  U.  S.  P.,  or  hy- 
drogen dioxide;  (3)  for  fetid  breath,  creosote;  (4)  in  foul  ulcers, 
potassium  permanganate,  hydrogen  dioxide,  or  formaldehyd. 

A  preservative  is  an  antiseptic  agent  used  to  prevent  microbic 
changes  (fermentation,  putrefaction)  in  organic  material,  such  as 
food,  medicines,  etc.  Preservatives  are  so  extensively  employed 
in  butter,  milk,  soups,  vegetables,  meat,  etc.,  that  it  is  possible 
to  ingest  a  large  quantity  of  one  preservative  or  small  doses  of 
each  of  several  preservatives  at  a  single  meal.  Many  of  them 
retard  decomposition  without  checking  the  activity  of  pathogenic 
germs. 

Sterilization  is  any  process  by  which  a  substance  is  made  germ- 
free.  It  usually  implies  destruction  of  germs  by  heat  at  ioo°  C. 
(2 1 20  F.)  or  higher.  Pasteurization  is  a  form  of  partial  steriliza- 
tion at  1600  F.  for  half  an  hour.     It  is  used  for  milk. 

The  ideal  antiseptic  or  disinfectant  for  use  about  the  body  is 
one  with  a  maximum  action  on  microorganisms  and  a  minimum 
action  on  the  body  tissues.  Of  blood  disinfectants,  quinine  in 
malaria  and  salvarsan  in  syphilis  would  seem  most  nearly  to 
approach  this  ideal;  though  their  destructive  effect  is  limited  to 
certain  organisms  only. 

The  germicidal  value  of  many  disinfectants  is  seriously  inter- 
fered with  by  organic  matter,  especially  blood-serum,  so  that  the 
germicide  that  is  strongest  in  the  test-tube  may  be  the  weakest 
when  in  contact  with  the  body  tissues.'  Moreover,  many  ger- 
micides are  decidedly  more  destructive  to  human  tissues  than  to 


460 


PHARMACOLOGY  AND  THERAPEUTICS 


germs,  so  that  their  use  may  result  in  a  lowering  of  the  local 
resistance  of  the  patient. 

Tests  with  Albuminous  Fluids.— On  mixing  hydrocele  fluid 
with  an  equal  quantity  of  an  antiseptic  solution  of  sodium  aurate, 
argyrol,  and  protargol  (Verhoeff,  1906),  and  of  collargol,  albargin, 
ichthargin,  argentamine,  largin,  and  argonin  (Derby,  1909),  the 
germicidal  effects  were  inhibited.  With  the  same  method, 
Verhoeff  and  Ellis  (1907)  found  that  lysol,  1  per  cent.,  creolin, 
1  per  cent.,  listerine,  100  per  cent.,  and  liquor  antisepticus, 
U.S.  P.,  100  per  cent.,  failed  to  kill  Staphylococcus  aureus  in  two 
hours.  The  last-named  authors  also  demonstrated  that  neither 
acetozone  1 :  1000,  alphozone  1 :  1000,  nor  zinc  sulphocarbolate, 
1  per  cent.,  mixed  with  solution  of  albumin,  was  successful  in 
sterilizing  typhoid  culture  in  twenty-four  hours;  and  that,  mixed 
with  albumin,  alkalol,  100  per  cent.,  borol,  50  per  cent.,  alkathy- 
mol,  100  per  cent.,  glycothymoline,  100  per  cent.,  zinc  sulpho- 
carbolate, 1  per  cent.,  and  cuprol,  5  per  cent.,  each  failed  to  de- 
stroy Staphylococcus  aureus  in  four  hours.  (See  also  under 
Silver.) 

Post  and  Nicoll  (19 10)  made  extensive  tests,  and  reported  the 
number  of  colonies  in  a  loopful  of  test  solution  after  different 
lengths  of  time. 

From  their  work  the  following  table  is  compiled : 


Solution-                               Strepto- 
coccus 

Gono- 
coccus 

P.VEUMO- 

coccus 

Bacillus 
Typhosus 

After 
What  Time 
in  Minutes 

I.  Silver  preparations: 

Argyrol.  50  per  cent 

00 
0 

3,000 
2,000 

00 
200 

O 
O 

One. 

Thirty. 

Argyrol,  10  per  cent 

CO 

11 

2,000 
0 

00 
7 

O 
O 

One. 

Thirty. 

Protargol,  10  per  cent 

600 
0 

200 

0 

^        0 

1,000 
0 

O 

One. 
Thirty. 

Silver  nitrate,  1  per  cent. .  .  . 

0             0 

0 

0 

One. 

Silver  nitrate,  1  :  1000 

0 
0 

0 
0 

><0 

20 
0 

500 

0 

One. 

Thirty. 

Silver  nitrate,  1  :  5000 

0 

0 
0 
0 

So 

1,000 
0 

00 
O 

One. 
Thirty. 

II.  Mercury  preparations: 

Mercuric  bichloride,  1  :  500 

2,000      3,000 
01 

3,000 
0 

O 
O 

One. 

Thirty. 

Mercuric  biniodide,  1  :  1000 

10             0 
0             0 

00 
4.000 

O 

0 

One. 

Thirty. 

DISINFECTANTS    AND    ANTISEPTICS 


461 


Solution 

Strepto- 
coccus 

Gono- 
coccus 

Pneumo- 
coccus 

Bacillus 
Typhosus 

After 
What  Time 
in  Minutes 

III.  Phenols: 

0 

0 

0 

0 

One. 

00 
500 

4,000 
0 

One. 
Thirty. 

4, 000 

1,000 

Trikresol,  1  per  cent 

O 

0 

0               0 

One. 

Trikresol,  0.3  per  cent 

4,000 

2,000 

10,000          2,000 

One. 

0 
0 

0 

One 

0             0              0 

Thirty. 

00 

12 

500         6.000            00 

One 

1,000 

4,000               CO 

Thirty. 

O 
O 

25 

0 

300  1           I 
0               0 

One 

Thirty. 

IV.  Iodine  preparations: 

Tincture  (7  per  cent.) 

O 

0 

0 

0 

One. 

Iodine 1    ] 

Potassium  iodide  .  .      1    [ 
Water.  .  .  .to  make  100   J 

O 

0 

0 

0 

One. 

V.  Formaldehyde  preparations: 
Liquor  formaldehydi,  U.S. P. 

O 

0 

0 

0 

One. 

Liquor  formaldehydi,    1   per 

10,000 

One 

1,000 

200 

SO 

Thirty. 

VI.  Alcohol: 

300 
3 

300 

0 

8,000 
8,000 

4,000 
2,000 

One 

Thirty. 

25 

0 

2,000 

300 

One 

50  per  cent 

0 

0 

0 

0 

One 

0 

0 

0 

0 

One. 

VII.  Miscellaneous: 

Tincture  of  green  soap 

0 

0 

0 

0  , 

One. 

Hydrogen  dioxide 

200 
0 

1,000 

0 

One 

0             0 

Thirty. 

Thiersch's  solution 

0 
0 

0        5,000 
0             0 

1 
^10,000 

O 

0    , 

One. 
Thirty. 

Potassium      permanganate, 
1  :  1000 

CO 

0 

3,000 

0 

Co 

2,000 

2,000 
O 

One. 
Thirty. 

Copper  sulphate,  1  per  cent. 

00 
5,000 

4,000 
2,000 

6,000 
4,000 

1 
3,000 

1,000 

One. 
Thirty. 

Boric  acid,  saturated  ( 1  :  18) 

00 
2,000 

3,000 

2,000 

10,000 

5,000 

00 

Co 

One. 

Thirty. 

Potassium     chlorate,    satu- 
rated, 6.6  per  cent 

CO 

5,000 

3,000 
2,000 

10,000 

5,000 

1 

Co 
CO 

One. 
Thirty. 

Glycerin 

Co 

CO 

One 

1,000 

4,000         00 

Thirty. 

Distilled  water 

00 

One 

462  PHARMACOLOGY   AND   THERAPEUTICS 

These  results  establish:  (1)  The  reliability  and  prompt 
action  of  a  few  simple  germicides,  such  as  tincture  of  green  soap, 
alcohol  in  solutions  above  50  per  cent.,  silver  nitrate  as  dilute  as 
1 :  1000,  the  iodine  solutions,  and  5  per  cent,  phenol.  (2)  The 
unreliability  of  many  agents  prevalently  supposed  to  be  effective 
germicides.  (3)  The  slow  action  of  mercuric  chloride,  though  when 
given  hours  to  act  it  is  effective  in  high  dilutions. 

Classification,  according  to  the  nature  of  the  agent: 

1.  Heat  and  cold. 

2.  Oxidizers. 

3.  Deoxidizers. 

4.  Free  halogens  and  their  compounds. 

5.  Metals  and  metallic  salts. 

6.  Miscellaneous  inorganic  compounds. 

7.  Phenol  and  its  allies. 

8.  Miscellaneous  organic  compounds. 

I.  HEAT  AND  COLD 

The  surest  disinfection  of  all  for  soiled  dressings  is  burning. 
In  the  preparation  of  sterile  dressings  there  is  nothing  more 
destructive  to  bacteria  or  more  penetrant  to  fabrics  than  super- 
heated steam — i.  e.,  steam  under  5  to  15  pounds  pressure,  which 
gives  it  a  temperature  of  2200  to  2300  F.  Doty,  at  the  New  York 
Quarantine  Laboratory,  found  that  a  moist  heat  of  2300  F.  killed 
all  germs  in  fifteen  minutes,  even  anthrax  spores,  and  even  when 
placed  in  the  center  of  large  and  tightly  rolled  bundles.  Next  in 
value  is  boiling  in  water  (2 1 20  F.) ,  as  of  instruments.  Liquids  may 
themselves  be  boiled,  unless  some  constituent  of  the  liquid  is 
destroyed  or  volatilized  by  heat.  These  methods  are  spoken  of 
as  methods  of  sterilization.  Pasteurization  is  incomplete  ster- 
ilization, the  liquidbeing  exposed  to  a  temperature  of  about  i6o°F. 
for  half  an  hour;  this  destroys  99  per  cent,  of  the  bacteria  of  milk. 
Dry  heat  is  less  effective  than  moist,  and  some  of  the  bacteria 
which  succumb  quickly  to  boiling  will  resist  for  a  time  a  dry  heat 
of  3500  or  4000  F. 

Cold  is  preservative,  but  not  sterilizing,  as  in  refrigerators  and 
cold  storage;  but  it  is  not  very  active  in  destroying  bacteria,  and 
more  or  less  bacterial  action  can  go  on  in  spite  of  a  temperature 
below  that  of  freezing.  In  ice-cream,  for  example,  kept  at  a  tem- 
perature of  —  5-8°F.  (— 210  C),  the  government  experts  found 
that  in  most  cases  the  number  of  living  bacteria  diminished  in  the 
cold  for  several  days,  then  showed  a  pronounced  rise  in  numbers, 
as  if  the  bacteria  had  become  inured  to  the  cold.  As  demonstrating 
the  failure  of  cold  to  check  microbic  growth,  one  sample  of 
ice-cream,  when  fresh,  showed  811,000  bacteria  per  gram;  after 


OXIDIZERS  463 

eighteen  hours,  1,010,509;  after  forty-two  hours,  3,349,733;  and 
after  sixty-six  hours,  4,405,000.  This  was  while  it  was  kept 
packed  in  a  freezing  mixture  of  ice  and  salt. 

Successful  cold  storage  requires  the  greatest  care  in  the  regu- 
lation of  both  temperature  and  moisture;  for  example,  fresh  eggs 
will  stand  a  temperature  of  280  F.,  but  after  about  three  months 
will  freeze  at  a  temperature  below  300  F. 

H.  OXIDIZERS 

These  act  by  liberating  oxygen,  and  in  their  action  are  them- 
selves quickly  destroyed.  They  are  very  inferior  disinfectants, 
but  are  effective  deodorizers.  They  readily  and  permanently 
destroy  many  colors,  and  are  used  as  bleaching-agents. 

1.  Aqua  hydrogenii  dioxidi,  peroxide  of  hydrogen,  H202,  is 
a  watery  liquid,  rather  unstable,  and  capable  of  yielding  10 
volumes  of  free  oxygen.  The  Pharmacopoeia  states  that  it  keeps 
better  if  a  pledget  of  cotton  is  used  to  stopper  the  bottle  instead 
of  a  cork.  It  destroys  cork,  rubber  tissue,  catgut,  etc.,  and  in 
contact  with  pus,  blood,  and  other  organic  liquids  splitsinto  water 
and  oxygen,  giving  off  the  oxygen  so  actively  that  it  effervesces 
and  produces  a  foam.  In  a  cavity  without  free  exit  this  gas  may 
burrow  into  the  tissues,  with  extension  of  the  infection.  It  is  a 
powerful  deodorizer,  and  in  dilution  with  not  more  than  one  or 
two  volumes  of  water,  is  a  valuable  germicide.  In  the  experiments 
of  the  Hygienic  Laboratory  (191 2)  cultures  of  typhoid  bacilli 
were  found  sterile  after  an  exposure  of  two  and  one-half  minutes 
to  50  per  cent,  solution.  (See  also  table  of  Post  and  Nicoll.)  It 
is  much  employed  as  a  gargle  or  mouth- wash,  as  in  diphtheria  or 
pyorrhoea  alveolaris,  or  for  deeply  furred  tongue,  and  as  a  surgical 
cleanser  in  pus  conditions.  The  author  has  employed  it  in  the 
colon  in  intestinal  putrefaction,  to  check  the  growth  of  anaerobic 
bacteria  by  liberating  oxygen ;  but  it  proved  too  irritating  to  the 
bowel.    It  is  also  irritant  in  the  throat. 

2.  Potassium  permanganate,  K2Mn208,  in  aqueous  solution, 
at  once  decomposes  when  it  comes  in  contact  with  organic  matter, 
giving  up  oxygen  without  effervescence  and  being  reduced  to  the 
brown,  insoluble  potassium  manganate.  It  is  a  chemic  antidote 
to  certain  oxidizable  poisons,  such  as  morphine,  phenol,  and 
hydrocyanic  acid,  is  a  local  irritant  and  stimulant,  as  in  persistent 
sinuses,  and  in  1  :  10,000  to  1 :  1000  solution,  is  an  antiseptic  and 
deodorizer,  as  of  foul  ulcers  and  foul  cancers.  The  crystals  of  the 
concentrated  solution  have  been  used  with  success  locally  in 
snake-bite.  Von  Adelung  (1913)  advises  a  2  per  cent,  solution  in 
ivy-poisoning. 

3.  Sodium  perborate,  containing  about  9  per  cent,  of  available 


464  PHARMACOLOGY  AND  THERAPEUTICS 

oxygen,  is  soluble  in  cold  water,  and  in  warm  or  moist  air  gives 
off  its  oxygen. 

4.  Chlorine  is  an  oxidizer,  as  it  unites  with  water  to  form  hydro- 
chloric acid,  and  sets  free  oxygen,  H20+2Cl  =  2HCl+0.  (See 
the  Halogen  Group.) 

m.    DEOXIDIZERS 

These  are  the  sulphite  group,  viz.,  sulphur  dioxide  and  sul- 
phurous acid,  sodium  sulphite,  sodium  bisulphite,  and  sodium 
thiosulphate  (hyposulphite).  The  sulphites  absorb  oxygen  to 
form  sulphates.  They  will  destroy  many  colors,  but  these  on 
exposure  to  the  air  tend  to  be  restored  through  reoxidation.  Fer- 
rous sulphate  is  of  this  group,  as  it  takes  up  oxygen;  its  chief  use 
is  in  water-closets,  sinks,  and  cess-pools. 

Sulphur  dioxide  (S02),  formed  by  burning  sulphur,  is  used 
for  the  disinfection  of  rooms.  It  bleaches  fabrics,  though  these 
may  slowly  regain  their  color  on  exposure  to  the  air.  As  a  disin- 
fectant it  is  not  very  efficient,  but  the  New  York  Department  of 
Health  allows  room  disinfection  with  eight  hours'  exposure  to  the 
fumes  of  4  pounds  of  sulphur  for  each  1000  cubic  feet  of  air-space. 
It  has  the  greatest  disinfectant  power  when  used  with  steam  or 
moist  air,  but  then  is  more  destructive  to  fabrics  and  colors.  The 
dry  sulphur  dioxide  is  effective  in  destroying  vermin,  but  it  does 
not  readily  penetrate  cracks. 

IV.  FREE  HALOGENS  AND  THEIR  COMPOUNDS 
Chlorine  and  the  Hypochlorites. — Chlorine  gas  is  set  free 
from  chlorinated  lime  on  contact  with  moisture,  or  it  may  be 
prepared  by  adding  dilute  sulphuric  acid  to  a  mixture  of  equal 
parts  of  manganese  dioxide  and  sodium  chloride.  Chlorine  water, 
0.4 per  cent.,  and  the  solution  of  sodium  hypochlorite  (Labarraque  's 
solution),  are  employed  as  gargles,  and  a  solution  of  potassium 
hypochlorite,  (eau  de  Javelle)  is  used  to  bleach  linen.  Antiformin 
is  an  alkaline  hypochlorite  used  to  dissolve  tissue,  blood,  pus,  and 
mucus  in  the  examination  of  sputum  for  tubercle  bacilli. 

A  favorite  procedure  for  the  disinfection  of  the  surgeon's 
hands  is  to  moisten  them  and  then  rub  them  together  with  a  little 
chlorinated  lime  and  washing-soda;  the  soluble  sodium  hypochlo- 
rite and  free  chlorine  are  generated,  and  serve  as  effective  skin 
germicides.  Chlorine  acts  as  a  disinfectant  by  uniting  with  the 
hydrogen  of  water  to  form  hydrochloric  acid,  with  the  liberation 
of  oxygen.  It  is  a  very  irritant  gas,  and  is  a  powerful  permanent 
bleaching-agent,  destroying  wall-paper,  fabrics,  etc. 

Chlorinated  lime,  CaCl2.Ca(OCl)2,  is  commonly  known  as 
''chloride  of  lime."     It  has  been  much  employed  in  privies, 


FREE  HALOGENS  AND  THEIR  COMPOUNDS        465 

sinks,  cess-pools,  etc.,  and  for  the  purification  of  drinking-water. 
For  the  latter  purpose  a  level  teaspoonful  of  the  powder  is  dis- 
solved in  a  pint  of  water,  and  of  this  one  teaspoonful  is  mixed 
with  two  gallons  of  the  water  to  be  purified,  i.  e.,  i  part  in 
2,000,000.  In  this  dilution  it  gives  no  taste.  Chlorinated  lime 
deteriorates  rapidly  on  exposure  to  air. 

Bromine  is  a  reddish-brown,  corrosive  liquid,  the  fumes  from 
which  are  very  irritating  to  the  respiratory  passages.  Severe 
bronchitis  and  laryngitis  have  occurred  from  the  breaking  of  a 
bottle  of  bromine  or  its  use  in  the  laboratory.  For  bromine 
burns  the  best  antidote  is  phenol,  which  forms  the  comparatively 
harmless  tribromphenol.  Bromine  water  is  employed  as  a 
gargle. 

Iodine  is  used  in  the  form  of  the  tincture  of  iodine  (iodine, 
7  per  cent.;  potassium  iodide,  5  per  cent.)  in  the  treatment 
of  ring- worm  and  other  parasitic  skin  diseases.  This  tincture 
or  an  alcoholic  solution  free  from  potassium  iodide  has  recently 
come  into  extensive  use  as  a  skin  disinfectant  preliminary  to 
operation.  It  is  highly  convenient  in  preparing  the  skin  for 
paracentesis  and  small  cuts,  and  for  major  surgery.  It  does  not 
injure  the  skin,  and  its  staining  soon  disappears.  Experiments 
have  shown  it  to  have  an  almost  instantaneous  destructive  effect 
upon  the  Staphylococcus  albus  of  the  skin  as  well  as  on  other 
bacteria.  The  work  of  Post  and  Nicoll  (see  Table) ,  Kinnaman, 
and  many  others  has  established  its  positive  disinfectant  value 
in  surgery.  Kinnaman  found  that  a  1  :  100  iodine  solution  de- 
stroyed the  Bacillus  tuberculosis  in  seven  minutes,  and  Bacillus 
prodigiosus  and  anthrax  bacillus  with  spores  in  ten  minutes. 
Churchill's  tincture  (16.5  per  cent,  of  iodine)  is  also  employed, 
but  such  strong  solutions  are  not  necessary.  E.  McDonald 
recommends  a  2  per  cent,  solution  in  carbon  tetrachloride. 

The  antiseptic  iodine  compounds  are  iodoform  and  certain 
iodine-containing  compounds  of  the  phenol  group,  viz.,  thymol 
iodide  (aristol),  europhen  and  losophan,  which  are  cresol  com- 
pounds, and  iodol  (tetra-iodo-pyrrhol).  These  were  designed 
to  have  the  iodoform  antiseptic  effect  without  its  disagreeable 
odor,  but  they  do  not  act  like  iodoform,  and  are  probably  anti- 
septic because  of  their  phenol  affinities  rather  than  because  of 
their  iodine  constituent.  Their  antiseptic  value  cannot,  there- 
fore, be  judged  by  their  iodine  percentage. 

Iodoform  is  a  yellow,  crystalline  powder,  insoluble  in  water, 
and  with  a  disagreeable,  persistent,  and  penetrating  odor.  It 
is  not  germicidal  except  in  contact  with  raw  tissues  or  wound 
secretions,  where  part  of  it  is  believed  to  change  into  iod-albumi- 
nates  and  di-iodo-di-acetylene.  Locally  it  is  irritant  and  may 
3° 


466  PHARMACOLOGY  AND   THERAPEUTICS 

cause  a  dermatitis  or  a  pustular  rash.  After  absorption  it  may 
have  simply  the  action  of  an  iodide,  or  give  poisonous  symptoms 
which  indicate  the  presence  of  unchanged  iodoform  in  the  blood. 
Iodoform  poisoning  usually  manifests  itself  in  one  of  three  forms, 
the  prominent  symptoms  being — (1)  Vomiting;  (2)  cerebral 
excitement  and  delirium;  or  (3)  cerebral  depression  with  melan- 
cholia. In  each  case  the  outcome  may  be  coma  and  collapse. 
The  poisoning  is  usually  due  to  the  packing  of  large  cavities  with 
strong  iodoform  gauze.  The  symptoms  of  hyperthyroidism 
have  been  reported.  In  tuberculous  sinuses  and  in  the  peritoneal 
cavity  in  tuberculous  peritonitis,  a  mixture  of  iodoform,  glycerin, 
and  ether,  incorrectly  called  "iodoform  emulsion,"  seems  to  be 
of  benefit;  though  the  belief  that  iodoform  exerts  a  specific 
effect  upon  the  tubercle  bacillus  has  no  experimental  support. 
It  has  also  been  thought  to  have  a  special  value  in  infections 
by  the  Bacillus  pyocyaneus.  To  remove  the  odor  of  iodoform 
from  the  hands,  Ricketts  recommends  vinegar. 

V.     METALS  AND  THEIR  COMPOUNDS 
These  combine  chemically  with  albumin  to  form  precipitates 
of  metallic  albuminates,  which  make  an  impenetrable  pellicle. 
Thus  the  metallic  salts  have  little  penetrating  power,  and  are 
readily  destroyed  by  the  body  fluids. 

Those  most  employed  as  antiseptics  and  disinfectants  are: 
Of  mercury — mercuric   chloride;   also,  slightly,  in   oint- 
ment form,  ammoniated  mercury  and  mercuric  oxide. 
Of  gold — sodium   aurate,   reported   by  Verhoeff   (1906) 

as  of  great  efficacy  and  little  toxicity. 
Of  silver — the  nitrate,  protargol,  argyrol,  etc. 
Of  copper  and  iron — the  sulphates. 
Of  zinc — the  sulphate  and  the  chloride. 
Of  aluminium — the  acetate,  made  fresh  in  solution. 
Of  bismuth — the  subiodide,   and  perhaps    slightly    the 
subnitrate  and  other  salts. 

The  pharmacology  of  the  metals  is  considered  further  on. 

VI.  MISCELLANEOUS  INORGANIC  COMPOUNDS 
Potassium  nitrate  (niter  or  saltpeter),  sodium  chloride, 
sodium  borate  (borax),  and  boric  acid  are  employed  as  food 
preservatives,  as  in  corned  beef,  ham,  butter,  etc.  Wiley  says 
that  the  small  quantities  of  salt  in  butter  are  not  preservative. 
Boric  acid,  a  crystalline  solid,  is  soluble  in  18  parts  of  water, 
16  of  alcohol,  and  5  of  glycerin,  and  volatilizes  when  its  solution 
is  boiled.  It  is  soothing  locally,  and  mildly  antiseptic.  Post 
and  Nicoll   (1907)    obtained  no   essential  germicidal  effect   in 


PHENOL   COMPOUNDS  467 

twenty  hours  from  saturated  aqueous  solutions;  but  Bernstein 
(1910)  has  demonstrated  that  it  has  some  power  to  check  the 
growth  of  yeasts  and  harmless  saprophytes,  though  only  slight 
effect  on  typhoid  and  other  pathogenic  germs.  It  is  more 
effective,  therefore,  as  a  preservative  than  as  a  disinfectant. 
About  the  body  it  possibly  acts  more  by  changing  the  reaction 
of  the  fluids  than  by  directly  retarding  the  microbic  growths. 

Its  solution  is  used  extensively  as  a  cleansing  application 
to  inflamed  mucous  membranes,  as  of  the  eye,  nose,  mouth,  vagina, 
etc.;  its  ointment,  as  an  application  to  eczematous  areas,  fungous 
skin  diseases,  and  burns;  and  the  acid  itself  as  a  dusting-powder 
in  the  shoes  in  sweating  of  the  feet.  It  is  almost  specific  against 
thrush  in  the  mouths  of  infants.  With  salicylic  acid  it  forms  the 
antiseptic  wash  "borosal"  or  Thiersch's  solution,  which  con- 
sists of  boric  acid,  8;  salicylic  acid,  2;  and  water,  to  make  1000. 
For  children  it  has  a  wide  range  of  application.  Boric  acid  and 
its  alkaline  salt,  sodium  borate  or  borax,  are  very  widely  em- 
ployed as  food  preservatives. 

Toxicology. — Boric  acid  has  been  the  cause  of  a  number  of 
cases  of  poisoning,  the  symptoms  being:  gastro-enteritis  with 
vomiting  and  diarrhea,  a  papular  eruption  on  the  skin,  general 
edema,  a  gray  line  on  the  gums,  and  central  depression  leading 
to  collapse.  Best  (1904)  gathered  from  the  literature  5  cases 
of  severe  poisoning  and  5  deaths.  Severe  symptoms  have  re- 
sulted from  irrigating  the  colon  -with  boric-acid  solution,  from 
packing  the  vagina,  the  ankle-joint,  etc.,  with  the  powder,  from 
washing  out  the  pleural  cavity,  a  lumbar  abscess,  etc. 

The  glycerite  of  boroglycerin,  a  thick  liquid  made  of  boric 
acid  and  glycerin,  is  used  on  vaginal  tampons  in  chronic  endome- 
tritis and  pelvic  inflammations. 

VII.  PHENOL  COMPOUNDS 
This  group  includes  phenol,  the  sulphocarbolates,  resorcinol, 
pyrogallol,  benzoic  acid,  salicylic  acid,  salol,  cinnamic  acid, 
cresol,  creosol,  guaiacol,  creosote,  tar,  oil  of  cade,  many  volatile 
oils,  camphor,  thymol,  aristol  (di-thymol  di-iodide),  europhen 
and  losophan  (iodine  compounds  of  cresol),  iodol  (tetra-iodo- 
pyrrhol),  naphthalene,  beta-naphthol,  etc. 


468 


PHARMACOLOGY  AND  THERAPEUTICS 


Creosol 


Guaiacol 


Cresol        g 


Salicylic 
Acid 


Benzoic 
Acid 


Pyro- 
gallol 

X 

OHydro- 
quinone 


Resorci- 
nol 


Pyro- 
catechin 


Phenol 


O 


Benzol 


Z 

w     Sodium  Phenol 
O     Sulphonate 
(Ethereal  Sul- 
phate) 


q,    Sodium 

w    Sulphocarbolate 


O 
u 

u    X 
\/ 

Z     Phenacetin 


K 

— \ 

B 

O 

\ 

/U     Anisic  Acid 
(Inactive  and 
passes  unchanged) 

K 

\ 

a 

o 

^Phloroglucin 
(not  antiseptic) 

o 
u 

\/ 

2    Acetanilid 


Cinnamic  Acid 


ttj 

U     Thymol 


U     Eugenol 


S/ \ 

0<f  >Anisol 


Europhen  =  Cresol  iodide. 
Losophan  =  Tri-iodo  cresol. 


X 
u 

Thymol 
Iodide 


D 


x 

Z    Iodol 
(Tetra- 
iodo- 
pyrrhol) 


Z 


Guaiacol 
Carbonate 


Beta- 
naphthol 


CJ  Trichlor- 
phenol 


Naphtalin 


Nosophen  =  Tetra-iodo-phenolphthalein 


:„/ 


\ 


Antinosine  =  Na  salt. 
Eudoxine  =  Bi  salt. 


PHENOL   COMPOUNDS  469 

The  drugs  of  this  group,  when  taken  internally,  tend  to  in- 
crease the  ethereal  sulphates  of  the  urine,  and  in  some  cases  may 
result  in  indicanuria.  They  are  less  affected  than  most  anti- 
septics by  organic  matter.  They  are  all  antiseptic,  antipyretic, 
and  analgesic.  Their  toxic  action  manifests  itself  by  depression 
of  the  respiratory  and  vasoconstrictor  centers,  coma,  and 
collapse. 

Benzoic  and  cinnamic  acids  and  their  salts  are  similar  to 
salicylic  acid  in  their  action,  though  less  effective  in  rheumatism. 
They  are  used  as  food  preservatives  and  even  in  very  minute 
quantities  retard  the  activity  of  the  digestive  ferments  (Sailer 
and  Farr).  The  cinnamates  have  been  employed  in  tuberculosis. 
Sodium  benToate  is  used  in  cystitis  to  acidify  and  disinfect  the 
urine.  Dakin  states  that  in  men  amounts  of  i  to  i}4  drams 
(4-10  gm.)  daily  for  two  or  three  days  are  practically  all  elimi- 
nated as  hippuric  acid.  Balsam  of  Peru,  which  contains  ben- 
zoates  and  cinnamates,  is  used  externally  in  chronic  skin  diseases; 
and,  in  the  form  of  "balsam  gauze,"  is  applied  to  ulcers  or  wounds 
as  a  stimulant  of  granulation. 

Benzoin,  which  is  also  a  balsam  containing  benzoates  and 
cinnamates,  is  very  fragrant.  It  is  employed  for  inhalation  in 
whooping-cough,  laryngitis,  nasopharyngitis,  bronchitis,  and 
pneumonia,  one  teaspoonful  of  the  compound  tincture  (benzoin, 
aloes,  storax,  and  tolu)  being  added  to  boiling  water  in  a  pitcher 
or  to  water  kept  boiling  in  a  croup-kettle,  and  the  steam  inhaled. 
Its  tincture  is  also  mixed  with  water  and  used  as  a  lotion  for 
the  skin  in  ivy-poisoning,  sunburn,  and  other  forms  of  dermatitis. 

Creosote,  which  is  an  empyreumatic  volatile  oil  obtained 
during  the  distillation  of  wood-tar,  contains  70  to  80  per  cent, 
of  guaiacol  with  cresol  and  creosol.  It  may  be  used  with  steam 
in  the  same  conditions  and  manner  as  the  compound  tincture 
of  benzoin,  or  it  may  be  dropped  on  the  sponge  of  a  zinc  respi- 
rator. Because  of  its  strong  odor,  it  is  employed  as  an  inhalant 
in  ozena,  fetid  bronchitis,  tuberculosis,  bronchiectasis,  gangrene 
of  lung,  etc.  Internally,  its  chief  employment  is  in  pulmonary 
tuberculosis  or  persistent  bronchitis,  in  dose  of  5  minims  (0.3  c.c). 
It  is  very  irritant  to  many  stomachs  and  disagreeable  to  the 
taste,  but  it  can  often  be  taken  in  milk  or  cod-liver  oil,  or  with  a 
strong  tasting  tincture,  such  as  the  compound  tincture  of  gen- 
tian. In  some  cases  of  tuberculosis  it  has  a  good  effect  on  appe- 
tite, fever,  and  night-sweats.  It  is  excreted  to  some  extent  by 
the  lungs,  as  noticed  in  the  breath,  but  there  is  no  evidence  of 
any  antiseptic  value  in  tubercle  tissue  or  in  the  bronchi.  Creosote 
carbonate  (the  carbonic  ester)  is  a  liquid  of  less  penetrating  odor 
and  less  biting  taste,  and  it  may  be  odorless  and  tasteless. 


47°  PHARMACOLOGY  AND  THERAPEUTICS 

Guaiacol,  the  chief  constituent  of  creosote,  is  an  oily  liquid, 
and  is  used  in  the  same  way  as  creosote;  dose,  5  minims  (0.3  c.c). 
It  is  also  employed  as  a  counterirritant  in  epididymitis  and  tuber- 
culous peritonitis.  Guaiacol  carbonate  (the  carbonic  ester)  is  a 
solid,  and  is  given  in  5-grain  (0.3  gm.)  capsules.  It  is  tasteless 
and  odorless  and  is  usually  well  borne  by  the  stomach. 

Cresol  is  much  more  germicidal  than  phenol.  Compound 
cresol  solution  (liquor  cresolis  compositus)  consists  of  50  per  cent, 
of  cresol  in  a  solution  of  soft  soap.  It  is  used  in  1  per  cent,  solu- 
tion in  water.  Proprietary  remedies  of  similar  nature  are  lysol 
and  creolin.  Fatal  poisoning  has  several  times  resulted  from 
confusion  over  the  name  lysol.  At  the  Hygienic  Laboratory 
the  disinfecting  value  in  inorganic  solutions  as  compared  with 
phenol  was,  for  compound  cresol  solution,  3;  for  creolin,  3.25;  for 
lysol,  2.12.  In  solutions  of  peptone  and  gelatin,  the  value  for 
compound  cresol  solution  was  1.87;  for  creolin,  2.52;  and  for 
lysol,  1.57. 

Resorcinol  (resorcin),  readily  soluble  in  water  and  alcohol, 
is  used  in  10  per  cent,  solution  as  a  scalp  wash  for  dandruff, 
and  in  skin  lotions  as  antiseptic  and  antipruritic.  In  the  stomach 
it  is  antifermentative,  dose,  5  grains  (0.3  gm.).  A  number  of 
cases  of  poisoning  are  reported,  even  from  the  application  of 
an  ointment. 

Pyrogallol  turns  brown  on  exposure  to  air.  It  is  employed 
in  fungous  skin  diseases.  Tar  and  oil  of  cade  are  added  to  oint- 
ments for  chronic  eczema  and  ring- worm.  The  syrup  of  tar 
(syrupus  picis  liquidag)  is  used  in  bronchitis  as  an  expectorant. 
Naphthalin  and  beta-naphthol  have  a  questionable  value  as 
intestinal  antiseptics;  dose,  5  grains  (0.3  gm.).  Fatalities 
are  reported  from  a  dose  of  1.75  gm.  of  naphthalin  given  for 
thread-worms,  and  from  moth-balls  eaten  by  children.  The 
iodine  phenol  compounds  are  probably  antiseptic  rather  in 
relation  to  their  phenol  constituent  than  to  their  iodine;  they 
were  brought  out  as  substitutes  for  iodoform.  Thymol  iodide 
(aristol)  is  much  employed  as  an  antiseptic  dusting-powder. 

Volatile  Oils. — Eucalyptol  is  one  of  the  strongest  antiseptics 
in  the  volatile  oil  group,  but,  owing  to  its  oily  nature,  cannot 
readily  be  employed  as  an  antiseptic.  Its  chief  use  is  as  an 
inhalant  in  respiratory  diseases,  coryza,  whooping-cough,  bron- 
chitis, etc.,  either  with  steam  or  by  respirator,  or  sprayed  from 
an  atomizer.  A  favorite  spray  consists  of  about  2  per  cent, 
each  of  eucalyptol,  camphor,  and  menthol,  dissolved  in  liquid 
paraffin.  Oil  of  cinnamon,  oil  of  cloves,  and  eugenol  are  used 
by  dentists. 

Antiseptic  solution  (liquor  antisepticus,  U.  S.  P.)    contains 


PHENOL,  OR  CARBOLIC  ACID  47 1 

2  per  cent,  of  boric  acid,  25  per  cent,  of  alcohol,  and  minute 
amounts  of  benzoic  acid,  thymol,  eucalyptol,  oil  of  peppermint, 
oil  of  wintergreen,  and  oil  of  thyme.  Diluted  with  water,  as 
this  must  be  for  application  to  mucous  membranes,  it  has  been 
shown  to  have  very  slight,  if  any,  antiseptic  power.  Its  chief 
use  is  as  a  pleasant  mouth-wash,  and  it  is  a  pharmacopeial  sub- 
stitute for  a  number  of  proprietaries  incorrectly  called  antiseptic, 
and  aptly  dubbed  by  Sollmann  the  "psychic  antiseptics." 

PHENOL,  OR  CARBOLIC  ACID 
Phenol  is  made  synthetically  and  is  also  obtained  from  coal-tar 
by  fractional  distillation.  It  is  a  crystalline  substance,  of  faintly 
acid  reaction,  freely  soluble  in  alcohol,  glycerin,  and  the  oils,  and 
in  20  parts  of  water.  The  crystals,  which  consist  of  about  96  per 
cent,  of  pure  phenol,  melt  on  warming,  and  remain  liquid  on  the 
addition  of  about  8  to  10  per  cent,  of  water.  The  official  "phenol 
liquef actum"  is  made  by  adding  10  parts  of  water  to  90  parts 
of  the  crystals.  This  forms  a  stock  solution  which  is  easier  to 
handle  than  the  crystals  regularly  employed;  but  if  water  is 
added  to  it,  the  phenol  separates  as  an  oily  liquid,  and  does  not 
go  into  solution  again  until  about  20  times  its  weight  of  water 
has  been  added.  In  other  words,  one  can  make  a  solution  of 
official  phenol  of  5  per  cent,  or  90  per  cent,  strength,  but  not  of 
any  strength  between.  If,  however,  the  phenol  is  previously 
dissolved  in  glycerin,  it  can  be  mixed  in  any  proportion  with 
water.  Phenol  precipitates  albumin,  gelatin,  and  collodion,  and 
makes  a  violet  color  with  ferric  salts. 
Preparations. — 

Phenol,  96  per  cent,  pure  phenol  in  crystal  form. 
Liquefied    phenol     (phenol    liquef  actum) — a    permanent 
liquid  made  by  mixing  9  parts  of  phenol  crystals  with 
1  of  water. 
Ointment,  3  per  cent,  in  white  petrolatum.    Phenol  tends 

to  separate  out  on  long  standing. 
Glycerite,  a  20  per  cent,  solution  in  glycerin. 
DobelVs  solution  (liquor  sodii  boratis  compositus,  N.  F.), 
which  contains  0.3  per  cent,  of  phenol  and  1.5  per  cent, 
each  of  sodium  bicarbonate  and  borax,  with  glycerin 
and  water. 
Pharmacologic   Action. — Microorganisms. — Phenol   exerts   a 
powerful  precipitating  effect  upon  protoplasm.    This  precipitate 
is  not  due  to  chemic  combination,  but  to  change  of  solvent,  i.  e., 
the  protoplasmic  elements  are  insoluble  in  a  solution  of  phenol. 
There  is  no  chemic  action,  and  the  phenol  can  be  washed  out 
of  the  tissues  by  a  solvent.    Since  it  is  not  chemically  combined, 


472  PHARMACOLOGY  AND  THERAPEUTICS 

it  has  greater  penetrating  power  than  most  of  the  disinfectants. 
Even  very  dilute  solutions,  i  1500,  cause  the  prompt  cessation 
of  motion  of  protozoa,  leukocytes,  spermatozoa,  and  ciliated 
epithelium,  the  protoplasm  of  the  cell  becoming  granular  and 
the  cell  soon  disintegrating. 

Bacteria,  as  they  have  a  cell- wall,  are  more  resistant;  yet 
even  these  are  penetrated  more  readily  by  phenol  than  by  most 
germicides.  The  susceptibility  to  the  phenol  varies  greatly 
with  the  different  kinds  of  bacteria,  and  the  spores  are  so  resistant 
that  they  require  to  be  exposed  to  strong  solutions  for  hours. 
Solutions  in  oil  or  alcohol  have  little  antiseptic  action;  for  the 
phenol  has  greater  affinity  for  oil  and  alcohol  than  for  the  water 
or  solution  of  salts  in  the  tissues,  consequently  does  not  pene- 
trate into  the  organism.  A  5  per  cent,  carbolic  ointment  made 
with  lard  will  go  rancid  in  spite  of  the  antiseptic. 

Very  dilute  solutions  tend  to  activate  both  unorganized  and 
organized  ferments;  stronger  solutions  retard  their  activity, 
and  especially  diminish  that  of  the  unorganized  ferments  of  the 
alimentary  tract. 

Locally,  phenol  is  somewhat  anesthetic,  tending  to  allay 
itching  and  pain.  It  is  absorbed  by  the  unbroken  skin,  but  much 
more  readily  by  mucous  membranes,  and  it  acts  on  the  sensory 
nerve-endings  to  produce  numbness,  though  not  complete 
analgesia.  There  may  also  be  tingling.  This  may  occur  from 
1  to  5  per  cent,  solutions,  as  when  the  hands  are  kept  wet  with 
a  solution  in  its  surgical  use.  It  thus  may  considerably  lessen 
pain,  but  usually  does  not  annul  it.  The  tingling  and  numb- 
ness may  last  half  an  hour  or  more.  Strong  phenol  produces 
a  burn,  the  pain  from  which  is  sometimes  not  noticeable  at  first 
on  account  of  the  anesthetic  action.  The  skin  becomes  white 
and  cold  from  constriction  of  the  vessels,  and  numb  from  paraly- 
sis of  the  ends  of  the  sensory  nerves;  later  it  becomes  red  and 
very  painful,  and  still  later  the  skin  may  dry  up  and  peel  off, 
or  the  superficial  tissues  may  slough  off  and  leave  a  painful, 
slowly  healing,   ulcerated  area. 

Both  weak  and  strong  solutions  applied  to  a  finger  or  toe  as 
wet  dressings  have  frequently  resulted  in  gangrene,  the  carbolic 
slowly  penetrating  the  tissues  and  causing  their  death,  while 
the  anesthetic  effect  prevents  the  warning  of  pain.  After  a  few 
hours  the  finger  is  found  to  be  white  and  dead,  and  it  subse- 
quently turns  black  on  the  surface.  It  is  sometimes  necessary 
to  amputate,  but  usually  not.  Strong  phenol  usually  causes 
pain  early,  so  that  measures  are  taken  to  stop  the  action,  hence 
gangrene  is  less  likely  than  from  weak  solutions. 

When  applied  to  a  wound,  phenol  solutions  coagulate  the 


PHENOL,    OR    CARBOLIC    ACID  473 

blood  and  protein  matters  and  form  a  pellicle  over  the  surface. 
This  pellicle  protects  the  germs,  so  that  phenol  may  have  an 
undesirable  effect  upon  the  body  cells  and  no  useful  one  on  the 
bacteria. 

On  mucous  membranes  there  are  the  same  anesthetic  and 
corrosive  actions  as  on  the  skin.  Weak  solutions  in  the  stomach 
are  somewhat  anesthetic  and  may  allay  vomiting. 

Systemically,  phenol  resembles  acetanilid  in  its  action,  but 
the  antiseptic  and  collapse  actions  predominate,  and  the  anti- 
pyretic action  is  less.  At  first  the  heart  is  stronger  from  direct 
stimulation  of  its  muscle;  later  this  is  weakened.  The  vaso- 
constrictor and  respiratory  centers  are  also  at  first  stimulated, 
then  markedly  depressed,  and  in  fever  the  temperature  is  lowered. 
But  collapse  is  readily  produced,  and  because  of  this  the  drug  is 
not  employed  for  its  systemic  effect.  We  must  understand 
these  effects,  however,  because  of  the  frequency  of  carbolic 
poisoning. 

In  a  study  of  the  effects  of  the  products  of  intestinal  putre- 
faction on  muscle,  F.  S.  Lee  found  that  in  a  solution  of  phenol, 
1 :  2000,  a  muscle  did  nearly  twice  as  much  work  as  before,  while 
in  solutions  of  1:1000  the  muscle  readily  became  fatigued  and 
did  less  work  (Herter) . 

Excretion  is  by  the  urine.  The  phenol  passes  out  partly 
unchanged  and  partly  oxidized  to  hydroquinone  and  pyrocat- 
echin  in  combination  as  ethereal  sulphates  and  glycuronates. 
The  urine  may  have  a  smoky  or  dusky  appearance,  or  may 
change  to  brownish-black  or  greenish-black  on  exposure  to  the 
air.  In  poisoning  practically  all  the  sulphates  of  the  urine  may 
be  in  the  form  of  ethereal  sulphates,  the  inorganic  sulphates 
completely  disappearing. 

Toxicology. — Phenol  is  usually  readily  obtainable,  and  is 
a  favorite  drug  for  committing  suicide.  Darlington  points  out 
that,  in  New  York  city  alone,  as  the  result  of  an  ordinance 
forbidding  the  sale  of  strong  carbolic,  the  number  of  suicides 
fell  from  343  in  a  year  to  36.  Its  recognition  is  usually  easy 
from  the  odor,  the  corroded  tongue  and  mouth  covered  with 
white  pellicle,  and  the  empty  bottle.  A  case  of  fatal  poisoning 
occurred  from  a  surgical  dressing  at  St.  Thomas'  Hospital, 
London. 

The  effects  from  a  poisonous  dose  may  be  of  three   types: 

1.  After  an  overwhelming  does  the  victim  becomes  un- 
conscious almost  immediately  and  dies  in  a  few  minutes  from 
shock. 

2.  From  good-sized  but  not  immediately  fatal  doses  the 
local  corrosion  is  marked,  and  there  is  rapid  absorption  of  a  large 


474  PHARMACOLOGY  AND  THERAPEUTICS 

quantity  of  the  drug.  The  patient  is  found  in  collapse,  perhaps 
unconscious,  with  muscular  tremors  and  twitchings  or  rarely 
convulsions.  Death  may  follow  in  a  few  hours  from  paralysis 
of  the  respiration,  the  patient  never  regaining  consciousness. 
Or  recovery  may  take  place,  with  extensive  corrosion  of  mouth, 
pharynx,  esophagus,  and  stomach.  Perforation  of  the  stomach 
may  occur,  or  months  later  cicatricial  contractions  in  any  part 
of  the  burned  area,  as  in  the  pharynx,  esophagus,  and  stomach. 
The  symptoms  of  poisoning  by  strong  phenol  are,  then: 
corrosion  of  the  alimentary  tract,  followed  by  collapse,  coma, 
and  perhaps  convulsions. 

3.  Where  weak  solutions  have  been  taken,  there  is  no  local 
corrosion,  but  there  is  a  gradual  onset  of  collapse  from  depres- 
sion of  centers  and  heart  muscle.  There  are  cold,  clammy  skin, 
nausea,  vomiting,  weak  shallow  breathing,  weak  rapid  pulse, 
mental  depression  and  anxiety,  or  coma,  and  prostration,  fol- 
lowed by  recovery  or  death.  The  sulphates  are  lacking  in  the 
urine,  so  that  when  barium  chloride  does  not  give  a  precipitate 
in  the  urine,  it  is  a  fair  conclusion  that  the  patient  is  poisoned 
with  phenol. 

Treatment  of  Poisoning. — 1.  Locally,  to  remove  the  phenol, 
the  best  application  is  alcohol.  But  a  bland  oil  or  fat  (olive, 
cottonseed,  or  linseed  oil,  or  lard  or  butter),  or  glycerin  or  vine- 
gar will  serve.  These  have  more  solvent  powers  for  carbolic 
than  the  liquids  of  the  protoplasm,  so  tend  not  only  to  prevent 
penetration,  but  also  to  extract  the  carbolic  from  the  tissues. 
For  the  stomach,  whisky  or  a  20  per  cent,  solution  of  alcohol 
may  be  employed;  but  this  must  be  washed  out  at  once,  as  the 
alcoholic  solution  of  phenol  is  very  readily  absorbed,  and  alcohol 
does  not  prevent  the  systemic  effects.  Clarke  and  Brown  have 
shown  that  lavage  with  water  is  an  effective  measure.  It  is 
said  that  lime  will  form  an  insoluble  compound,  and  that  potas- 
sium permanganate  will  oxidize  and  destroy  the  phenol,  but  these 
substances  can  hardly  be  given  in  sufficient  quantity.  After 
thorough  lavage,  demulcents,  such  as  oils,  milk,  and  white  of 
egg,  may  be  swallowed.  The  burns,  ulcers,  or  cicatricial  con- 
tractions must  later  on  be  treated  like  any  other  burns  or  ulcers 
or  cicatrices. 

2.  System  ically. — On  account  of  the  disappearance  of  the 
inorganic  sulphates  from  the  urine  and  their  replacement  by 
ethereal  sulphates,  it  has  been  believed  that  the  alkaline  sul- 
phates would  combine  with  the  phenol  to  form  non-toxic  sulpho- 
carbolates  (phenolsulphonates) ,  and  so  lessen  its  activity  and 
promote  its  excretion.  (The  phenolsulphonates  are  not  formed 
in  a  test-tube  or  in  the  stomach,  though  they  are  slowly  formed 


MISCELLANEOUS    ORGANIC   COMPOUNDS  475 

in  the  body.)  On  this  theory  sulphates  have  been  given  by 
mouth  in  carbolic  poisoning,  and  sodium  sulphate  in  1  to  2  per 
cent,  solution  has  been  administered  intravenously.  Sollmann 
and  Brown  (1907)  studied  this  matter  very  carefully  by  an 
extended  series  of  experiments;  and  found  that  the  combination 
takes  place  too  slowly  for  any  useful  antidotal  effect,  whether 
the  sulphates  are  given  before,  with,  or  after  the  phenol,  and 
whether  they  are  given  by  mouth  or  intravenously;  therefore  they 
are  not  chemic  antidotes.  A  saline  infusion  may,  however,  be 
of  great  value  in  the  treatment  of  collapse;  and  it  would  be  well 
to  add  1  per  cent,  of  sodium  sulphate  to  this.  The  treatment  is 
that  for  collapse. 

Therapeutics. — Strong  phenol  is  used  as  a  powerful  local 
antiseptic  in  dog-bite,  carbuncles,  small  infected  cavities,  and 
other  small  superficial  wounds.  Its  continued  action  or  pene- 
tration may  be  checked  by  alcohol.  It  is  sometimes  injected 
into  cyst  cavities  to  cause  an  inflammation  and  obliteration  of 
the  cyst  (bursitis,  hydrocele),  and  also  into  hemorrhoids. 

For  ordinary  antiseptic  purposes,  as  washing  a  wound,  disin- 
fecting excreta,  towels,  bedding,  etc.,  solutions  of  1  to  5  per  cent, 
strength  are  employed  for  from  one-half  to  two  hours.  They 
are  more  antiseptic  and  more  penetrating  than  the  ordinary 
solutions  of  bichloride  of  mercury,  and  they  do  no  harm  to 
fabrics  or  metal  dishes.  Locally,  it  is  added  to  lotions  to  allay 
itching. 

Bacelli  (191 1)  tabulates  94  cases  of  tetanus  treated  intraven- 
ously by  increasing  doses'of  0.3  to  1.5  gm.  in  twenty-four  hours, 
in  2  per  cent,  solution.  He  found  that  in  190  reported  cases  the 
mortality  was  only  17.36  per  cent.  The  method  would  seem  to 
be  highly  dangerous;  but  Bacelli  thinks  that  patients  with 
tetanus  are  exceptionally  tolerant  to  phenol. 

Vm.  MISCELLANEOUS  ORGANIC  COMPOUNDS 
Ichthyol  and  thiol  are  oily-looking  sulphur  compounds  which 
are  soluble  in  water  and  the  oils,  and  not  in  alcohol.  Ichthyol 
is  obtained  from  a  shale,  and  -thiol  is  prepared  synthetically. 
Their  3  to  5  per  cent,  solutions  are  applied  externally  as  soothing 
lotions,  as  in  bad  sunburn.  Their  50  per  cent,  solution  is  painted 
over  infected  areas  to  promote  absorption  of  serous  or  fibrinous 
exudates.  Ichthyol  ointment,  10  to  50  per  cent.,  is  applied  to 
lessen  glandular  or  joint  swellings  and  in  erysipelas.  It  has  been 
thought  that  it  may  favor  the  resistance  of  the  tissues  by  inducing 
a  local  gathering  of  leukocytes.  Vaginal  tampons  bearing  a  solu- 
tion of  10  to  30  per  cent,  in  glycerin  are  largely  employed  in  cases  of 


476  PHARMACOLOGY   AND   THERAPEUTICS 

chronic  endometritis  and  chronic  pelvic  inflammations.  Ichthyol 
has  an  unpleasant  odor,  while  thiol  is  nearly  odorless. 

Internally,  ichthyol  is  employed  in  cases  of  intestinal  putre- 
factive toxemia  as  an  intestinal  disinfectant,  dose,  3  to  5  grains 
(0.2-0.3  gm-)  m  a  capsule  or  enteric  pill.  It  is  slightly  laxative. 
Ichthyol  enters  into  "Bum  Mixture."  (See  Hoffmann's  Ano- 
dyne.) 

Methylene-blue  is  little  used  as  an  antiseptic.  It  turns  the 
urine  a  bluish-green,  a  fact  that  has  been  made  use  of  as  a  func- 
tional test  for  the  kidneys.  It  has  been  injected  into  recurrent 
or  inoperable  carcinomata,  but  without  any  noteworthy  effects. 
After  its  ingestion  by  mouth,  Brauer  found  large  quantities  of  it 
in  the  bile.  The  ordinary  commercial  article  usually  contains 
zinc,  and  if  taken  internally,  may  cause  vomiting.  The  author 
saw  a  case  of  acute  gastro-enteritis  follow  a  capsule  of  methyl- 
blue,  prescribed  by  the  physician  in  mistake  for  methylene-blue. 

Formaldehyd  (HCOH)  is  a  gas,  and  its  aqueous  solution, 
containing  not  less  than  37  per  cent,  by  weight  of  absolute 
formaldehyd,  is  official  under  the  name  of  "Liquor  Formalde- 
hydi. "  This  solution  should  be  neutral  or  only  faintly  acid 
to  litmus,  showing  the  absence  of  formic  or  other  acids.  It  is 
marketed  under  the  name  of  "Formalin,"  and  usually  contains 
about  10  per  cent,  of  methyl  alcohol  to  facilitate  solution  and 
prevent  polymerization.  At  ordinary  temperature  it  gives  off 
formaldehyd  gas.  On  cooling  the  solution  below  68°  F.  and 
drying,  a  white  powder  results.  This  is  known  as  paraform 
(trioxymethylene) ,  and  is  a  polymeric  form  of  formaldehyd. 
On  gently  heating,  this  is  reconverted  into  gaseous  formaldehyd. 

Formaldehyd  is  pungent  and  very  irritating  to  eyes,  nose, 
and  throat.  It  is  rendered  inert  by  alkalies,  especially  ammonia; 
it  reduces  Fehling's  solution;  it  attacks  metals  (instruments); 
it  hardens  tissues,  blood,  and  gelatin  (blood  on  the  hands  be- 
comes darkened  and  difficult  to  wash  off).  This  last  property 
has  been  made  use  of  to  harden  gelatin  capsules  so  that  they 
would  pass  through  the  stomach  into  the  intestine  before  dis- 
solving (glutol  capsules) ;  but  the  degree  of  hardening  is  uncertain. 
It  is  employed  as  a  hardening  and  fixing  agent  for  anatomic 
and  biologic  specimens,  and  is  used  as  an  arterial  injection  for 
embalming  the  dead  and  for  preserving  cadavers  for  dissection. 
It  may  be  employed  for  fixing  blood-smears.  An  important 
property  is  that  of  preventing  the  coagulation  of  serum  albumin 
by  heat,  as  in  urine. 

Formaldehyd  is  a  powerful  disinfectant.  It  is  much  employed 
as  a  preservative  of  foods.  One  part  in  20,000  cannot  be  detected 
by  its  odor,  yet  will  keep  milk  for  several  days.    In  1:50,000 


MISCELLANEOUS    ORGANIC    COMPOUNDS  477 

strength  it  retards  the  growth  of  the  lactic-acid  bacillus,  but  has 
little  effect  on  the  colon  or  typhoid  bacillus  (Vaughan).  Bur- 
nam  (191 2)  found  that  a  1:20,000  solution  retarded,  but  did 
not  destroy,  typhoid  bacillus  and  streptococcus;  but  that  a 
1 :  1000  solution  killed  colon,  typhoid,  and  pyocyaneus  bacilli, 
streptococcus  and  Staphylococcus  aureus  in  twenty-four  hours. 
It  is  used  as  a  preservative  of  cider,  fruit-juices,  and  canned  foods, 
and  is  employed  as  our  most  valuable  general  disinfectant  for 
sick-rooms. 

The  gas  may  be  generated — (1)  By  warming  the  solution;  (2) 
by  heating  paraf ormaldehyd ;  (3)  by  adding  one  pound  of  fresh 
quicklime  to  a  mixture  of  6  ounces  of  aluminum  sulphate  and 
8  ounces  of  formaldehyd  solution,  as  advised  by  the  New  York 
Health  Department,  this  amount  yielding  enough  gas  to  dis- 
infect a  room  containing  1000  cubic  feet;  (4)  but  the  best  method 
of  all  is  to  add  compressed  blocks  of  potassium  permanganate 
to  the  formaldehyd  solution  in  a  large  pail.  The  gas  is  given  off 
with  violent  ebullition  (formanganate  disinfector). 

The  exposure  to  the  gas  should  be  from  twelve  to  twenty-four 
hours.  It  has  little  penetrating  power,  so  may  fail  to  enter  the 
cracks  in  the  floor  or  penetrate  a  mattress.  In  the  presence  of 
moisture,  as  steam,  it  is  more  effective  than  when  dry.  If  the 
temperature  of  the  room  is  below  520  F.,  it  may  polymerize  into 
paraform.  It  does  not  kill  vermin.  Doty  and  others  report 
that  bedbugs,  roaches,  mosquitos,  or  even  rats,  rabbits,  and 
guinea-pigs,  were  alive  after  many  hours'  exposure.  The  gas  is 
immediately  neutralized  by  ammonia  gas. 

Formaldehyd  is  somewhat  used  for  sterilizing  absorbent 
cotton,  sutures,  and  surgical  dressings;  but,  on  account  of  its 
action  on  metals,  its  irritating  vapor,  and  its  bad  effect  on  the 
hands,  is  limited  in  its  use  as  a  surgical  disinfectant. 

Locally,  the  solution  of  formaldehyd  has  been  used  in  fungous 
skin  diseases  (favus,  sycosis,  ring- worm),  to  disinfect  foul  ulcers 
and  cancers,  to  check  local  sweating,  and  to  harden  and  dry  up 
small  growths,  such  as  moles,  condylomata,  and  even  cancer. 
Daniel  says  that  formalin  rubbed  into  warts  with  a  stick  makes 
them  come  off  without  leaving  a  scar.  In  very  weak  solution 
it  has  been  employed  as  an  antiseptic  to  mucous  membranes,  as 
in  catarrh  of  the  nose,  throat,  or  vagina — usually  with  other 
mucous  membrane  antiseptics.  Recently  it  has  been  recom- 
mended to  leave  a  weak  solution  of  formaldehyd  in  the  pleural 
cavity  after  paracentesis  for  pleurisy  with  effusion. 

Poisoning. — There  are  a  number  of  reported  cases  of  poisoning 
from  its  ingestion  by  mouth,  with  intense  irritation  of  the  esoph- 
agus and  stomach,  vomiting,  diarrhea,  coma,  and  collapse.    The 


478  PHARMACOLOGY   AND   THERAPEUTICS 

kidneys  are  also  irritated,  as  shown  by  albuminuria,  bloody  urine, 
or  suppression.  The  urine  may  contain  albumin  and  formic  acid. 
The  chemic  antidote  for  the  stomach  is  ammonia,  well  diluted, 
and  followed  by  demulcents,  such  as  bland  oils,  mucilaginous 
drinks,  starch  water,  milk,  and  white  of  eggs.  Collapse  is  treated 
in  the  usual  way. 

4NH3     +     6HCOH     =     N4(CH2)fi     +     6H20 

Ammonia  Formaldehyd  Hexamethyl-  Water 

enamine 

Hexamethylenamine,  N4(CH2)6,  known  also  as  urotropin, 
cystogen,  formin,  etc.,  is  an  artificial  alkaloid  made  by  combining 
6  molecules  of  HCOH  with  4  of  ammonia.  It  occurs  in  crystals 
which  are  soluble  in  1.2  parts  of  water  and  in  10  parts  of  alcohol. 
It  is  incompatible  with  acids  and  salts  of  acid  reaction,  and  with 
mercuric  chloride. 

Hexamethylenamine  has  no  local  action.  A  50  per  cent, 
solution  is  non-irritant  (Burnam).  It  is  rapidly  absorbed,  has  no 
essential  systemic  action,  and  appears  in  the  urine  in  a  few  minutes. 
It  has  been  found  in  the  ear  discharge  in  a  case  of  middle-ear 
disease,  and  in  the  milk,  bile,  pancreatic  juice,  blood,  saliva, 
synovial  fluid,  nasal  and  bronchial  secretions,  pleural  effusions, 
and  cerebrospinal  fluid  of  human  beings.  It  is  not  essentially 
diuretic,  and  has  no  power  to  dissolve  uric-acid  calculi.  It  came 
into  use  as  a  urinary  disinfectant,  its  value  depending  on  its 
ability  to  liberate  formaldehyd.    This  it  tends  to  do  in  acid  fluids. 

Jordan  (191 1)  gave  10  grains  (0.7  gm.)  three  times  a  day,  and 
found  that  when  the  urine  was  alkaline  or  of  low  acidity,  there  was 
no  germicidal  effect.  When  the  urine  was  alkaline,  he  could 
obtain  the  effect  by  administering  acid  sodium  phosphate  to 
acidify  the  urine;  and  when  the  urine  was  acid,  he  could  lessen 
the  effect  by  administering  potassium  citrate.  Sollmann  (1908) 
found  that  in  alkaline  urine  it  developed  antiseptic  properties, 
i.  e.,  formaldehyd  in  antiseptic  amounts,  only  after  one  and  a  half 
hours.  In  ammoniacal  urine  formaldehyd  cannot  exist,  as  it  has 
great  chemic  affinity  for  ammonia.  When  formaldehyd  is  present, 
the  urine  will  reduce  Fehling's  solution. 

At  Johns  Hopkins  Hospital  hexamethylenamine  was  found  to 
lessen  greatly  the  number  of  typhoid  bacilli  in  the  urine  of  typhoid 
patients,  though  not  to  render  the  urine  completely  germ  free.  In 
pyelitis  and  in  cystitis  it  is  disinfectant,  though  in  Bacillus  coli 
infections  and  in  gonorrhea  it  has  sometimes  failed  completely  to 
clear  the  urine.  L'Esperance  found  formaldehyd  present  in  the 
urine  in  5  2  per  cent,  of  cases  taking  hexamethylenamine.  Burnam 
(191 2)  tested  the  urines  of  some  of  Howard  A.  Kelly 's  cases  after 
they  were  given  hexamethylenamine.    Of  10  cases  taking  5  to  10 


MISCELLANEOUS    ORGANIC   COMPOUNDS  479 

grains  (0.3-0.7  gm.)  three  times  a  day,  only  2  showed  formalde- 
hyd ;  some  others  gave  the  reaction  when  the  dose  was  increased 
to  20  to  30  grains  (1.3-2  gm.)  every  four  or  six  hours;  and  some 
gave  no  reaction,  even  after  a  dose  of  100  grains  (6.7  gm.).  He 
found  it  in  some  cases  with  alkaline  urine,  and  failed  to  get  it  in 
some  with  acid  urine.  In  some  patients  the  concentration  in 
the  urine  reached  as  high  as  1 :  5000. 

The  use  of  hexamethylenamine  in  therapeutics  depends  solely 
on  its  power  to  liberate  formaldehyd.  Its  appearance  in  a  se- 
cretion does  not,  therefore,  indicate  its  antiseptic  value  in  that 
secretion,  for  when  it  does  not  liberate  formaldehyd  its  antiseptic 
effect  is  very  slight.  Hence,  the  report  by  Crowe  (1908)  that  it 
appears  in  other  secretions  than  the  urine,  and  the  assumption 
that  it  was  therefore  antiseptic  in  these  secretions,  though  alka- 
line, make  it  imperative  to  study  the  matter  more  thoroughly. 

Crowe  (191 2)  tabulates  the  uses  of  hexamethylenamine  as 
follows  :  (1)  Infections  of  the  geni to-urinary  tract  and  typhoid 
bacilluria.  (2)  Infections  of  the  bile-ducts  and  gall-bladder. 
(3)  Infections  of  the  cerebrospinal  system  (meningitis,  poliomyel- 
itis, etc.).  (4)  Infections  of  the  respiratory  tract  (rhinitis,  ton- 
sillitis, bronchitis,  infections  of  nasal  sinuses,  etc.,  but  not  in 
pneumonia  and  tuberculosis).  He  found  it  in  the  cerebrospinal 
fluid  in  half  to  one  hour  after  its  administration.  In  man  he 
estimated  that  100  to  150  grains  (6.7-10  gm.)  a  day  would 
suffice  to  check  the  growth  of  organisms  in  the  spinal  fluid,  and 
that  75  grains  (5  gm.)  a  day  would  do  the  same  in  the  bile. 

Flexner  and  Clark  (191 1)  found  that  the  experimental  trans- 
mission of  poliomyelitis  was  checked  or  retarded  in  its  period  of 
incubation. 

Burnam  (191 2)  tested  the  secretions  other  than  urine  in  cer- 
tain cases  of  Dr.  Howard  A.  Kelly.  The  following  are  his  results 
from  Hehner's  test,  which  reacts  very  delicately  to  both  hexa- 
methylenamine and  formaldehyd.  (The  urine  was  the  only 
secretion  that  was  positive  with  Burnam's  test,  which  reacts 
with  formaldehyd  in  amounts  above  1 : 1 50,000,  but  not  with 
hexamethylenamine.) 

1.  The  Bile. — In  10  cases  of  biliary  fistula,  40  grains  (4  gm.) 
a  day  gave  only  a  faint  test,  though  bile  containing  as  much  as 
1 :  50,000  gives  a  sharp  reaction. 

2.  The  Saliva. — Only  faint  traces. 

3.  Sputum. — In  three  cases  of  bronchitis,  absolutely  none  of 
the  drug  present., 

4.  Cerebrospinal  Fluid. — In  one  case  getting  15  grains  (1  gm.) 
every  three  hours  for  twenty-four  hours,  4  c.c.  of  the  spinal  fluid 
showed  mere  traces. 


480  PHARMACOLOGY  AND  THERAPEUTICS 

In  all  these  fluids  the  drug,  either  hexamethylenamine  or 
formaldehyd,  was  not  present  in  amounts  above  1: 150,000, 
and  therefore  was  absolutely  without  antiseptic  value.  Hanzlik 
(iqio)  showed  that  there  was  no  formaldehyd  set  free  in  the 
saliva,  and  Fullerton  points  out  that  Sollmann's  demonstra- 
tion of  the  time  required  for  the  development  of  formaldehyd 
in  alkaline  liquids  would  forbid  its  formation  in  any  free-running 
secretion.  It  is  to  be  noted  that  formaldehyd  in  the  urine  may 
lessen  the  heat  test  for  albumin  and  the  test  for  indican,  and  may 
give  Fehling's  reaction. 

Untoward  Effects. — In  acid  urine  it  sometimes  so  increases  the 
acidity  as  to  make  the  urine  irritating,  or  sets  free  enough  for- 
maldehyd to  do  this;  and  marked  vesical  pain,  frequent  burning 
micturition,  bloody  urine,  and  defoliation  of  the  bladder  mucous 
membrane  have  been  reported.  The  kidneys  are  also  irritated 
at  times,  though  Richardson  (1899)  showed  that  in  the  presence 
of  an  existing  nephritis  there  was  no  increase  in  albumin  or  casts. 
Coleman  (1903)  reported  the  following  untoward  sequelae:  irri- 
tation of  stomach,  diarrhea,  and  abdominal  pain;  irritation  of 
kidneys  and  bladder,  with  hematuria  and  hemoglobinuria;  head- 
ache, ringing  in  ears;  and  a  skin  rash  like  that  of  measles.  Crowe 
reports  that  of  95  cases  getting  an  average  dosage  of  75  grains 
(5  gm.)  a  day,  7  developed  painful  micturition  and  hematuria. 
He  has  noted  also  skin  rashes,  acute  catarrh  of  mucous  membranes, 
and  gastric  irritation.  Frothingham  (1909)  reported  that  very 
large  doses  could  be  given  to  guinea-pigs  without  injury,  though 
their  stomachs  were  prone  to  become  ulcerated  and  to  bleed.  He 
sometimes  got  necrosis  at  the  site  of  a  hypodermatic  injection  of 
the  drug.  Burnam  says  that  a  50  per  cent,  solution  is  not  irritant 
locally. 

Therapeutics  and  Administration. — From  the  above  it  is  seen 
that  there  is  no  question  of  the  frequent  value  of  hexamethylena- 
mine as  a  disinfectant  in  the  urinary  tract.  For  this  purpose  it 
is  given  in  amounts  of  5  to  20  grains  (0.3-1.3  gm.)  three  times  a 
day  with  large  quantities  of  water  to  favor  elimination  by  the 
kidneys.  If  the  urine  is  alkaline,  it  may  be  acidified  by  acid 
sodium  phosphate,  but  this  must  not  be  given  at  the  same  time 
as  the  drug,  as  they  are  chemically  incompatible. 

But  there  is  great  question  as  to  its  value  for  any  other  pur- 
pose, such  as  colds  and  gall-bladder  and  meningeal  infections. 
In  these  cases — (1)  Very  large  doses  must  be  employed;  (2)  it  is 
probable  that  their  effect  is  very  little  if  any;  and  (3)  they  are  not 
without  risk  of  harm.  Crowe  gave  50  to  100  grains  (3.3-6.7  gm.) 
in  one  liter  of  normal  saline  daily  by  rectum  by  the  drop  irrigation 
method,  and  had  no  sign  of  intestinal  irritation  even  after  two 


PRESERVATIVES  481 

weeks.  Also,  as  the  drug  is  practically  tasteless,  he  gave  it  by 
adding  2  or  3  grains  (0.12-0.2  gm.)  to  each  ounce  (30  c.c.)  of 
fluid  taken  by  the  patient.  Bagby  recommends  it  highly  in 
pellagra. 

THERAPEUTIC   CLASSIFICATION   OF   DISINFECTANTS 
I.  GENERAL  DISINFECTANTS  AND  DEODORIZERS 

(a)  Used  in  dry  form — for  water-closets,  sinks,  and  cess-pools, 
copperas  (ferrous  sulphate),  naphthalin  (tar  balls),  lime,  and 
chlorinated  lime  are  preferred  because  cheap. 

(b)  Used  in  solution — for  utensils,  excreta,  bedding,  etc.,  from 
the  sick-room.  For  basins,  chambers,  bed-pans,  etc.,  a  solution 
of  mercuric  bichloride,  zinc  chloride,  or  phenol  is  employed.  The 
zinc  chloride  is  odorless,  an  obvious  advantage  over  carbolic, 
whose  universally  recognized  odor  suggests  unpleasant  sick- 
room experience.  In  full  strength,  Piatt's  Chlorides,  a  proprie- 
tary, failed  to  kill  the  typhoid  bacillus  in  ten  minutes  (Hygienic 
Bulletin  No.  82).    The  bichloride  destroys  metallic  utensils. 

The  urine,  feces,  or  sputum  may  be  received  in,  and  mixed 
with,  a  3  per  cent,  solution  of  carbolic,  a  1 :  5000  solution  of 
mercuric  bichloride,  or  a  1  per  cent,  solution  of  zinc  chloride.  The 
mixture  should  be  allowed  to  stand  for  half  an  hour. 

(c)  Used  as  gas — for  rooms  and  contents,  bedding,  clothes, 
etc.,  formaldehyd,  sulphur  dioxide,  free  chlorine,  the  creosols  of 
smoke  (burning  sugar,  coffee,  brown  paper,  etc.).  It  is  difficult 
to  find  a  gaseous  disinfectant  that  will  penetrate  through  bed- 
clothes and  mattresses,  and  into  the  cracks  of  a  wall  or  floor. 

II.  PRESERVATIVES 

1.  Pharmaceutic — alcohol,  glycerin,  sugar,  benzoin,  aromatic 
oils,  boric  acid. 

2.  Foods — boric  acid,  borax,  saltpeter  (KN03),  salicylic  acid, 
formaldehyd,  sodium  chloride  (butter,  ham,  fish,  corned  beef), 
smoke  (smoked  beef),  sugar,  vinegar. 

3.  Anatomic  material — formaldehyd,  acetic  acid,  arsenic, 
alcohol,  glycerin,  potassium  bichromate. 

4.  Antitoxins,  vaccines — glycerin,  trichlorphenol,  phenol,  tri- 
kresol. 

Alcohol  is  the  most  useful  preservative  for  vegetable  drugs  in 
solution;  thus  tinctures  and  fluidextracts  keep  well,  while  aqueous 
solutions,  such  as  infusions,  do  not.  A  saturated  solution  of  sugar 
is  antiseptic,  as  seen  in  jams  and  medicinal  syrups;  syrups  less 
than  saturated  will  ferment  or  mold.  Glycerin  is  a  much-used 
preservative  of  vegetable  extracts.  To  preserve  meat,  borax  and 
31 


482  PHARMACOLOGY  AND   THERAPEUTICS 

saltpeter  are  used,  or  the  meat  is  salted  or  smoked  (as  ham, 
corned  beef,  smoked  beef,  etc.) ;  through  exposure  to  smoke  it 
absorbs  creosols  and  other  wood-tar  constituents.  Boric  acid, 
salicylic  acid,  and  formaldehyd  are  added  to  various  canned  and 
preserved  foods  and  to  milk.  Boric  acid  will  also  retard  the  com- 
mon fungus  growth  in  solutions  of  chemicals,  such  as  cocaine.  A 
too  much  used  preservative  of  milk  is  formaldehyd,  which,  in 
amounts  sufficient  to  keep  milk  for  a  week,  cannot  be  detected  by 
its  odor.  Lard  may  be  kept  from  becoming  rancid  for  a  time  by 
the  presence  of  benzoin,  as  in  benzoinated  lard.  Butter  keeps 
better  when  it  is  salted.  Chemically  preserved  foods  (embalmed 
foods)  are  usually  less  readily  digested  than  normally,  as  the  pre- 
servatives interfere  with  the  activity  of  the  digestive  ferments. 

HI.  DISINFECTANTS  FOR  SURGICAL  SUPPLIES 
For  utensils,  surgical  instruments,  and  dressings  the  best  of  all 
disinfectants  is  live,  superheated  steam  at  2200  to  235°F.  The 
next  best  is  dry  heat.  Instruments  can  be  boiled  with  water,  or 
placed  in  5  per  cent,  phenol  or  70  per  cent,  alcohol,  or  a  mixture 
of  phenol  and  alcohol.  Catgut  is  sterilized  by  boiling  with  cumol 
or  alcohol.  Dressings,  absorbent  cotton,  etc.,  may  be  sterilized 
by  dry  heat  or  formaldehyd. 

IV.  DISINFECTANTS  FOR  LOCAL  USE   ABOUT  THE  BODY 

1.  Skin. — (a)  For  the  Patient's  Skin,  Preliminary  to  Operation. 
— Scrubbing  with  soft  soap  and  application  of  tincture  of  iodine. 

(b)  For  the  Surgeon's  Hands. — Chlorine,  generated  by  rub- 
bing the  hands  with  chlorinated  lime  and  washing  soda;  potassium 
permanganate,  1 :  5000,  followed  by  oxalic  acid  to  remove  the 
brown  stains;  tincture  of  iodine;  alcohol;  3  per  cent,  phenol;  and 
mercuric  bichloride  1 :  2000.  It  is  of  no  use  to  dash  the  hands  into 
an  antiseptic  solution,  then  think  them  disinfected.  The  bichlo- 
ride of  mercury,  for  example,  requires  many  minutes  for  its 
action. 

(c)  For  the  Obstetrician's  Hands. — A  half  per  cent,  solution 
of  lysol  or  of  the  official  compound  solution  of  cresol.  Both  are 
rather  soapy  and  serve  as  lubricants  in  vaginal  examinations. 
Their  slipperiness  interferes  somewhat  in  the  handling  of  instru- 
ments.- 

All  antiseptics  for  the  hands  and  skin  are  preceded  by  thorough 
scrubbing  with  green  soap  and  hot  water.  This  acts  by  removing 
the  loose  epithelium  and  bacteria,  and  is  probably  of  quite  as 
much  value  as  most  of  the  antiseptics  in  freeing  the  skin  from 
germ  life.    In  open  wounds  there  are  very  few  antiseptics  that  do 


THE   HEAVY   METALS  483 

not  harm  the  tissues  of  the  host  more  than  they  do  those  of  the 
bacteria. 

(d)  In  Skin  Diseases. — The  organic  substances,  tar,  oil  of 
cade,  naphthalin,  balsam  of  Peru,  benzoin,  resorcinol,  salicylic 
acid,  pyrogallol,  ichthyol,  formaldehyd;  and  the  inorganic  sub- 
stances, mercuric  chloride,  ammoniated  mercury,  mercurial  oint- 
ment, boric  acid,  sulphur,  iodine,  and  its  compounds. 

2.  In  eye — boric  acid,  silver  salts,  copper  sulphate,  mercuric 
oxide  ointment. 

3.  In  nose — camphor,  menthol,  oil  of  eucalyptus,  boric  acid, 
the  silver  salts,  peroxide  of  hydrogen. 

4.  In  mouth  and  throat — boric  acid,  the  silver  salts,  hydrogen 
dioxide,  mercuric  chloride,  ferric  chloride,  glycerin,  iodine. 

5.  In  urethra  and  bladder — the  silver  salts,  potassium  per- 
manganate, zinc  sulphate. 

6.  In  vagina — compound  solution  of  cresol,  creolin,  lysol, 
phenol,  ichthyol,  mercuric  chloride,  boroglycerin. 

7.  In  rectum — boric  acid,  silver  salts,  quinine  bisulphate. 

8.  In  larynx  and  bronchi  by  inhalation — oil  of  eucalyptus, 
camphor,  menthol,  creosote,  benzoin. 

9.  In  open  wounds — iodoform  and  the  phenol  iodine  com- 
pounds, mercuric  chloride,  phenol,  potassium  permanganate, 
balsam  of  Peru  (gauze),  ichthyol,  aluminium  acetate,  bismuth 
subiodide,  zinc  sulphate  (in  red  wash),  boric  and  salicylic  acids 
(Thiersch's  solution),  hydrogen  dioxide. 

V.  DISINFECTANTS  TO  BE  GIVEN  BY  MOUTH 

For  the  stomach — salicylic  acid,  10  grains  (0.7  gm.),  resor- 
cinol, 10  grains  (0.7  gm.),  sodium  sulphocarbolate,  10  grains 
(0.7  gm.),  creosote,  5  minims  (0.3  c.c),  aromatic  oils,  5  minims 
(0.3  c.c). 

For  the  intestines — aspirin,  salol,  naphthalin,  betanaphthol,  or 
ichthyol,  in  dose  of  5  grains  (0.3  gm.). 

After  absorption — to  have  a  remote  local  effect  in  their  excre- 
tion. 

(a)  Urinary  tract — certain  of  the  volatile  oil  series  (turpentine, 
balsam  of  copaiba,  oil  of  sandalwood,  cubebs,  buchu,  uva-ursi), 
hexamethylenamine  (urotropin),  benzoates,  salol. 

(b)  Respiratory  tract — volatile  oil  series  (turpentine,  terpin 
hydrate,  cubebs,  tar,  and  creosote),  hexamethylenamine(P). 

(c)  In  other  secretions  or  body  fluids — hexamethylenamine  (?). 

THE   HEAVY   METALS 

The  heavy  metals,  though  differing  markedly  in  some  of  their 
,  details  of  action  and  in  their  therapeutic  uses,  have  certain  phar- 


484  PHARMACOLOGY  AND  THERAPEUTICS 

macologic  actions  in  common.  Their  salts  tend  to  precipitate 
proteins,  forming  metallic  albuminates  of  variable  composition. 
The  salts  which  are  most  readily  dissociable  into  ions  act  most 
rapidly  and  tend  to  be  irritant.  They  may  even  be  caustic,  caus- 
ing death  of  tissue.  The  soluble  salts,  through  precipitation  of 
the  proteins  of  the  cells,  tend  to  be  astringent.  The  organic  pre- 
parations and  double  salts  tend  to  dissociate  less  easily  and  have 
less  local  action.  The  salts  of  inorganic  acids  tend  to  be  especially 
astringent  from  the  setting  free  of  the  acid. 

The  absorption  of  most  of  the  salts  is  slow,  and  their  excretion 
also  very  slow,  and  chronic  poisoning  by  some  of  the  metals  may 
follow  the  repeated  ingestion  for  many  days  of  very  minute 
quantities.  They  are  mostly  excreted  by  the  kidneys  and  the 
gastro-intestinal  tract;  and  in  the  poisoning  these  organs  tend  to 
be  inflamed. 

The  nervous  system  is  also  sensitive  to  the  metals,  peripheral 
neuritis,  excitability,  and  scleroses  in  the  brain  or  cord  being 
sometimes  manifestations  of  metallic  poisoning. 

MERCURY 
There  are  many  official  salts  and  preparations  of  mercury 
(hydrargyrum),  and  their  actions  and  uses  are  so  distinct  that 
they  may  well  be  considered  separately  according  to  their  ther- 
apeutic uses.  The  therapeutic  classes  are:  (1)  The  disinfectants. 
(2)  The  antisyphilitics.  (3)  The  cathartics.  (4)  Those  with 
special  uses. 

I.     The  Disinfectants 

(a)  Mercuric  chloride,  hydrargyri  chloridum  corrosivum, 
HgClo,  known  also  as  bichloride  of  mercury  or  corrosive  sub- 
limate, is  soluble  in  13  parts  of  water  and  3  of  alcohol.  The  solu- 
tion in  water  takes  place  slowly,  but  is  hastened  by  the  addition 
of  some  sodium  or  ammonium  chloride.  These  chlorides,  however, 
prevent  the  ready  dissociation  of  the  bichloride  into  ions,  and 
reduce  the  antiseptic  power  about  half  (Wolf).  In  Paul  and 
Krony's  experiments  the  number  of  anthrax  colonies  obtained 
after  six  minutes'  exposure  of  the  spores  to  bichloride,  1 :  60,  was 
8,  while  when  the  bichloride  was  mixed  with  an  equal  amount  of 
sodium  chloride,  they  obtained  32  colonies,  and  with  four  times 
as  much  sodium  chloride,  382  colonies.  These  chlorides  retard 
correspondingly  the  precipitation  of  albumin.  Mercuric  chloride 
has  many  incompatibles,  such  as  alkaloids,  alkalies,  lime-water, 
and  soap.  A  large  basin  of  bichloride  antiseptic  solution  will  be 
destroyed  by  a  very  small  amount  of  green  soap.  It  is  also  de- 
composed by  carbonates,  silicates,  and  sulphates,  such  as  occur 


THE    ANTISYPHILITICS  485 

in  the  natural  waters;  so  that  in  making  its  solutions,  distilled 
water  is  preferable. 

A  solution  of  i :  1,000,000  will  kill  protozoa,  a  solution  of  1 :  10,- 
000  will  prevent  the  growth  of  molds  and  bacteria.  It  takes  some 
time  for  their  destruction,  however,  and  it  is  absurd  to  suppose 
an  instrument  or  the  hands  to  be  sterilized  by  a  momentary 
dipping  or  rinsing  of  them  in  the  solution.  The  spores  of  bacteria 
are  much  more  resistant  than  the  germs  themselves.  The  bi- 
chloride acts  by  forming  a  chemical  precipitate  with  the  proteins 
of  the  protoplasm;  as  a  consequence,  it  has  little  penetrating 
power  and  is  quickly  rendered  practically  useless  by  albuminous 
fluids.  It  may  coagulate  an  albuminous  envelop  about  bacteria 
without  killing  them. 

Locally,  its  solutions  are  astringent  and  irritating,  and,  if 
strong,  are  corrosive  to  the  tissues.  Even  very  weak  solutions,  if 
much  used,  cause  roughening  and  discoloration  of  the  skin,  and 
in  the  form  of  a  continuous  wet  dressing  may  produce  a  dermatitis 
or  a  pustular  rash. 

In  1 :  4000  to  1 :  1000  aqueous  solution  mercuric  chloride  has 
been  one  of  the  most  used  antiseptics  for  the  hands  of  the  surgeon 
or  obstetrician,  for  the  skin  preliminary  to  operation,  for  infected 
wounds,  for  excreta,  and  in  1 :  10,000  solution  as  an  irrigation  in 
any  accessible  body  cavity,  as  throat,  vagina,  uterus,  bladder,  etc. 
It  is  also  used  in  fungus  and  bacterial  skin  diseases  and  for  pubic 
lice. 

Harrington's  solution,  as  used  at  the  Mayo  Clinic,  is  mercuric 
chloride,  0.8  gm.;  hydrochloric  acid,  60  gm.;  distilled  water, 
300gm.;  alcohol,  640  gm.;  i.  e.,  1:1250  by  weight. 

(b)  The  other  mercurial  antiseptics  are  less  employed.  The 
ointment  of  mercury  in  two  strengths,  viz.,  mercurial  ointment, 
50  per  cent.,  and  blue  ointment,  33  per  cent.,  and  the  ointment  of 
ammoniated  mercury  (white  precipitate  ointment)  are  employed 
in  fungous  and  bacterial  skin  diseases;  the  ointment  of  the 
nitrate  of  mercury  (citrine  ointment)  is  used  especially  for  ring- 
worm. The  ointment  of  the  yellow  oxide  is  preferred  about  the 
eye,  as  in  blepharitis,  conjunctivitis,  and  keratitis.  The  solution 
of  the  nitrate  has  been  used  as  a  caustic. 


II.     The   Antisyphilitics 

As  local  applications  to  venereal  sores,  mercuric  chloride, 
calomel,  black  wash  (lotto  nigra  is  calomel,  1  grain,  to  lime-water, 
1  ounce),  yellow  wash  (lotio  flava  is  bichloride,  \]/2  grain,  to  lime- 
water,  1  ounce)  and  the  ointments  of  mercury  and  ammoniated 
mercury,  are  all  employed. 

For  the  systemic  action  mercury  is  administered  by  inunction, 


486  PHARMACOLOGY  AND   THERAPEUTICS 

by  mouth,  and  by  hypodermatic  injection.  For  inunction  the 
mercurial  ointment  is  regularly  employed,  but  it  is  dirty  and  tends 
to  irritate  the  skin,  and  its  absorption  is  uncertain.  Ten  to  30 
grains  are  rubbed  well  into  the  softer  parts  of  the  skin  every  day 
or  two,  a  new  area  being  chosen  for  each  successive  inunction,  on 
account  of  irritation.  The  favorite  sites  are  the  inner  surfaces  of 
the  thighs  and  arms,  and  the  chest,  back,  and  abdomen.  Oleateof 
mercury  and  white  precipitate  ointment  are  occasionally  used 
instead  of  mercurial  ointment. 

By  mouth,  the  favorites  are  the  biniodide,  y^- grain,  and  the 
protoiodide,  \  grain,  and  for  children  the  mercury  with  chalk, 
1  grain.  The  bichloride,  dose,  ■£%  grain,  is  sometimes  given  in  a 
mixture  with  potassium  iodide,  with  which,  however, it  changes  to 
the  biniodide. 

For  deep  intramuscular  injection  into  the  upper  part  of  the 
gluteal  muscles,  the  insoluble  mercuric  salicylate  and  the  soluble 
benzoate  are  the  favorites.  The  former  is  insoluble  in  water  or 
oil,  and  is  used  in  10  to  20  per  cent,  admixture  with  liquid 
paraffin.  According  to  Lascoff,  it  makes  the  best  mixture  if  half 
a  per  cent,  of  lanolin  is  added.  The  dose  is  y£  to  \Y2  grains 
(0.03-0.1  gm.),  injected  into  the  buttock  once  a  week,  or  every 
five  days,  or  in  urgent  cases'  every  second  day.  More  or  less 
soreness,  as  of  a  bruise,  may  follow  the  injection  for  a  day  or  two, 
and  occasionally  headache,  languor,  and  diarrhea.  The  benzoate 
is  soluble  and  more  readily  absorbed,  so  must  be  administered 
every  second  day.  Precaution  must  be  taken  that  the  drug  is  not 
injected  directly  into  a  vein.  The  advantages  of  the  hypoder- 
matic method  are:  the  exact  dosage,  the  cleanliness,  and  the  close 
supervision  of  the  patient  which  are  gained  by  the  necessarily 
frequent  visits. 

III.     The    Cathartics    (See  under  Cathartics) 
IV.     Those  with  Special  Uses,  Other  Than  Those  Mentioned 

Mercury  subsulphate  (turpeth  mineral), as  an  emetic  in  croup. 
Dose,  2  grains  (0.13  gm.)  for  a  child  of  six. 

Calomel,  in  croupous  laryngitis;  5  to  20  grains  volatilized  on 
a  tin  plate  or  in  a  teaspoon,  and  inhaled — not  often  employed  at 
the  present  time. 

Calomel  as  a  Diuretic. — Calomel  may  be  of  value  at  the  begin- 
ning of  a  course  of  diuresis.  If  it  is  absorbed,  it  tends  to  irritate 
kidney  cells,  but,  as  a  matter  of  fact,  most  of  it  fails  of  absorption 
and  passes  out  by  the  rectum.  It  is  probable  that  much  of  the 
value  of  calomel  in  inducing  diuresis  is  due  to  the  relief  of  the 
splanchnic  circulation  through  purging.  Gray's  Diuretic  Pill 
consists  of  1  grain  (0.06  gm.)  each  of  calomel,  digitalis,  and  squill. 


MERCURY  487 

The  use  of  mercury  succinimide,  i  grain  (0.0012  gm.)  every 
second  day  for  30  injections,  has  been  recommended  in  tuber- 
culosis, but  has  not  proved  curative. 

Systemic  Action  of  Mercury  Salts. — After  absorption  mercury 
becomes  generally  distributed  throughout  the  body,  but  is  espe- 
cially stored  up  in  the  liver  and  the  kidneys. 

In  its  therapeutic  use  it  has  little  direct  action  on  any  of  the 
tissues ;  but  an  improvement  in  the  blood  and  nutritional  state 
is  believed  to  follow  repeated  small  doses. 

Elimination. — It  is  eliminated  by  the  salivary  glands,  stomach, 
liver,  kidneys,  colon,  and  rectum,  and  in  the  urine,  sweat,  and 
milk.  The  major  portion  passes  through  the  walls  of  the  colon 
and  upper  rectum  and  may  cause  considerable  irritation  or  actual 
colitis.  Koldewijn  applied  mercurial  ointment  to  cows,  and  was 
unable  to  find  mercury  in  the  milk ;  but  Haas  found  that  -3V  grain 
(0.0005  gm.)  of  mercuric  chloride  given  three  times  a  day  to  the 
mothers  of  syphilitic  infants  had  a  slight  but  positive  remedial 
effect  on  the  nursing  child.  It  is  said  that  mercury  has  been 
detected  in  the  tissues  six  months  after  its  administration  has 
been  stopped. 

Kidneys. — Mercuric  chloride  has  a  special  destructive  action 
upon  the  epithelium  of  the  convoluted  tubules,  and  has  been 
employed  to  produce  experimental  tubular  nephritis.  In  acute 
poisoning  there  may  be  a  violent  exudative  nephritis;  in  subacute 
or  chronic  poisoning  there  may  be  a  diffuse  nephritis,  the  destruc- 
tive effects  in  the  tubules  being  followed  by  changes  in  the  glom- 
eruli and  increase  of  connective  tissue.  Calomel  is  frequently 
employed  to  aid  other  diuretics;  but  it  probably  acts  by  catharsis 
to  relieve  the  kidneys,  rather  than  by  direct  irritation  of  the 
kidney-cells. 

Toxicology  of  Mercury. — 1.  The  mildest  form  of  poisoning 
has  for  its  prominent  feature  "mercurial  stomatitis,"  or,  as  it  is 
commonly  called,  "salivation."  This  is  a  not  uncommon  result 
of  mercury  salts  administered  as  remedies,  even  a  grain  or  two  of 
calomel  being  sufficient  in  some  cases  to  produce  it.  It  is  much 
more  readily  produced  in  nephritis  than  when  the  kidneys  are 
unimpaired.  In  several  instances  the  author  has  seen  salivation 
in  nephritis  from  two  or  three  compound  cathartic  pills,  each  of 
which  contains  one  grain  of  calomel. 

The  symptoms  of  "salivation"  are:  profuse  flow  of  saliva, 
metallic  taste,  very  foul  breath,  coated  swollen  tongue,  soreness 
or  ulceration  of  the  gums  or  inside  of  the  mouth,  soreness  of  the 
tooth-sockets  (test  patient  by  having  him  hit  teeth  together),  and 
loosening  of  the  teeth.  The  profuse  salivation  may  go  on  to 
inflammation  of  the  salivary  glands  and  necrosis  of  parts  of  the 


488  PHARMACOLOGY  AND  THERAPEUTICS 

mouth  and  jaw.  In  addition  the  patient  feels  ill  and  there  may  be 
headache,  lassitude,  muscular  weakness,  and  diarrhea;  occasion- 
ally there  is  constipation.  As  a  prophylactic  during  the  adminis- 
tration of  mercury  salts,  and  as  treatment  for  mercurial  stoma- 
titis, a  mouth-wash  of  a  saturated  solution  of  potassium  chlorate 
with  a  little  tincture  of  myrrh  is  recommended. 

2.  Severe  acute  poisoning  is  usually  due  to  the  bichloride, 
either  from  swallowing  the  tablets  or  a  solution  (often  with 
suicidal  intent),  or  from  the  retention  of  strong  solutions  used  as 
uterine  or  vaginal  douches.  Taken  by  mouth,  bichloride  gives  a 
strongly  metallic  and  astringent  taste.  If  the  swallowed  liquid  is 
strong  enough,  there  is  local  corrosion  of  mouth,  esophagus,  and 
stomach,  followed  by  abdominal  pain  and  vomiting.  There  may 
be  copious  serous  or  bloody  stools,  albuminous  or  bloody  urine,  or 
suppression  of  the  urine,  delirium,  coma,  collapse,  and  death  or 
slow  recovery.  Postmortem  examination  shows  the  local  cor- 
rosion of  the  upper  part  of  the  alimentary  tract,  and  also  acute 
colitis,  acute  proctitis,  and  acute  nephritis.  In  the  enterocolitis 
there  may  be  extensive  necrosis;  in  the  nephritis  there  are  fatty 
degeneration  and  necrosis  of  the  cells  of  the  convoluted  tubules. 
Pericarditis  is  reported.  There  is  occasionally  a  period  of  a  day 
or  two  before  the  onset  of  the  symptoms. 

If  the  patient  does  not  die  quickly,  he  may  be  ill  for  days  or 
weeks,  with  marked  salivation,  inflammatory  and  gangrenous 
lesions  of  the  pharynx,  cheeks,  and  hard  palate,  spongy  and 
broken-down  gums,  loss  of  the  teeth,  gastritis,  colitis,  and  nephri- 
tis. He  may  eventually  recover,  or  may  die  of  uremia  or  colitis 
or  general  prostration.  Arterial  pressure  may  be  high  until  col- 
lapse sets  in.  Of  five  such  cases  due  to  antiseptic  tablets  seen  in 
two  years  by  the  author,  three  died  and  two  recovered. 

Treatment. — At  the  outset,  after  bichloride  is  swallowed, 
white  of  egg  or  milk  should  be  given  to  form  non-corrosive 
albuminates;  and  these  should  promptly  be  removed  from 
the  stomach  by  lavage  or  vomiting  to  prevent  absorption. 
Bland  oils  and  other  demulcents  should  then  be  given  to  soothe 
damaged  membranes.  The  systemic  treatment  is  symptomatic. 
As  the  mouth,  colon,  and  kidney  symptoms  develop,  these  require 
vigorous  treatment.  Potassium  chlorate  and  myrrh  make  a 
favorite  mouth- wash,  and  if  the  mouth  is  foul,  peroxide  of  hydro- 
gen. The  colitis  and  nephritis  require  the  usual  treatment  for 
these  conditions. 

Chronic  Poisoning. — This  is  seen  among  makers  of  mirrors, 
barometers,  thermometers,  etc.  The  writer  saw  a  case  in  a  man 
who  had  used  cinnabar  (mercuric  sulphide)  in  an  Indian  make-up. 
Besides  the  salivation,  the  poisoning  shows  the  usual  effects  of 


LEAD  489 

the  heavy  metals  on  the  nutrition,  the  alimentary  tract,  the  ner- 
vous system,  and  the  blood.  These  effects  are  loss  of  appetite, 
nausea,  and  other  derangements  of  digestion,  constipation  or 
diarrhea,  colic,  anemia,  loss  of  flesh  and  strength,  and  aching  in 
bones  and  joints.  There  may  be  a  general  cachexia.  There  is  no 
line  on  the  gums,  as  in  lead-poisoning.  The  effect  on  the  nervous 
system  may  be  pronounced.  There  are:  a  tremor  of  the  hands 
and  lips  or  the  whole  body,  irritability  of  temper,  fear,  hallucin- 
ations, loss  of  memory,  and  perhaps  a  peripheral  neuritis  (Starr 
says  rare,  if  occurs  at  all).  The  diagnosis  is  confirmed  by  finding 
mercury  in  the  urine  or  feces. 

The  treatment  is  removal  of  the  patient  from  exposure  to  the 
mercury,  potassium  iodide  to  promote  elimination  (Oliver  thinks 
this  is  useless),  and  care  for  the  nervous  condition,  the  malnu- 
trition, the  anemia,  and  the  salivation. 

During  the  treatment  of  syphilis  a  slight  sore  throat  or  mouth 
due  to  mercury  may  sometimes  be  attributed  to  the  disease,  and 
may  persist  until  the  mercury  is  stopped.  Busch  says  that  mer- 
cury is  contraindicated  in  Addison's  disease. 

LEAD 

The  lead  (plumbum)  salts  are  not  much  employed  in  medicine. 

Preparations. — (a)  For  External  Use. — The  acetate  and  sub- 
acetate  are  antiseptic  and  astringent  and  are  soothing  to  wounds 
and  bruises.  Liquor  plumbi  subacetatis  (Goulard's  extract)  con- 
tains about  25  per  cent,  of  lead  subacetate.  Liquor  plumbi 
subacetatis  dilutus  (lead-water)  is  a  4  per  cent,  solution  of  the 
liquor.  It  is  used  as  a  wet  dressing  for  wounds  and  bruises,  and 
as  a  soothing  application  in  skin  diseases,  sunburn,  ivy  poison, 
and  eczema. 

Lead  and  opium  wash  (Lotio  Plumbi  et  Opii,  N.  F.)  contains 
lead  acetate,  128  grains  (16  gm.),  tincture  of  opium,  4  drams 
(15  c.c),  and  water  to  make  one  pint  (475  c.c). 

Lead  oleate  is  a  sticky,  insoluble  mass,  which  is  used  as  the 
mechanical  basis  of  plasters.  It  is  known  as  "lead  plaster."  From 
the  prolonged  application  of  plasters  it  has  caused  poisoning. 

Lead  sulphate  is  present  as  a  sediment  in  liquor  alumini  aceta- 
tis  (Burow  's  solution) ,  when  this  is  made  of  lead  acetate  and  alum. 
It  should  be  filtered  off,  as  it  has  caused  poisoning. 

(b)  For  internal  use  the  only  salt  employed  is  the  acetate, 
dose,  2  grains  (0.13  gm.).  Its  only  use  is  to  overcome  intractable 
diarrhea,  as  from  tuberculous  enteritis  or  colitis,  and  to  induce  a 
temporary  obstipation,  as  in  operations  about  the  anus  or  rectum. 
Two  grains  (0.13  gm.)  are  often  given  in  a  pill  with  1  grain  (0.06 
gm.)  of  opium. 


490  PHARMACOLOGY  AND  THERAPEUTICS 

Toxicology.— Though  lead  has  but  little  use  in  therapeutics, 
it  is  of  importance  to  physicians  because  of  the  frequency  of 
chronic  lead-poisoning  or  plumbism.  This  occurs  very  commonly 
among  painters  and  plumbers  and  other  workers  in  lead  (type, 
lead  pipe,  shot,  pottery  glazing,  enamelware,  etc.),  and  is  one  of 
the  diseases  often  met  with  in  clinics  and  hospitals.  It  may  even 
result  from  hair-washes  containing  lead  acetate,  from  water  that 
has  stood  in  lead  pipes,  from  canned  food  with  lead  in  the  solder 
of  the  cans,  from  wall-paper,  or  from  the  prolonged  application 
of  plasters  (with  lead  plaster  base)  to  the  skin.  Gottheil  reports 
a  case  of  death  from  the  sediment  (lead  sulphate)  in  Burow's 
solution  made  with  lead  acetate  and  alum. 

The  symptoms  are:  Anemia  and  wasting,  foul  breath,  bad 
taste  in  the  mouth,  loss  of  appetite,  especially  in  the  morning, 
gastric  and  intestinal  disturbances,  pains  in  the  joints  and  bones, 
and  spots  before  the  eyes.  Sailer  and  Speese  found  almost  com- 
plete absence  of  gastric  juice  in  10  out  of  12  subjects.  Chronic 
nephritis  is  very  common,  and  the  arterial  pressure  tends  to  be 
high.  In  rabbits,  Charteris  found  that  lead  carbonate  produced 
a  marked  anemia,  with  degeneration  of  both  the  leukoblastic  and 
the  erythroblastic  elements  of  the  bone-marrow.  In  addition  there 
are  usually  certain  manifestations  which  are  characteristic  of  lead, 
and  determine  the  type  of  complaint  to  the  physician,  viz. : 

1.  Colic. — Lead  colic,  painter's  colic — true  colic  with  marked 
constipation.  The  patient  is  relieved  by  pressure  upon  the 
abdomen  and  will  often  be  found  lying  prone  upon  a  pillow  or 
bolster.  Mosse  found  that  the  injection  of  lead  acetate  into  ani- 
mals caused  degenerative  changes  in  the  sympathetic  ganglia  of 
the  abdomen.  And  it  has  generally  been  believed  that  the  con- 
stipation is  due  to  irritation  of  the  splanchnic  inhibitory  nerves  of 
the  intestine.  But  both  the  constipation  and  the  colic  are  prob- 
ably due  to  an  irregular  irritation  of  the  vagus  nerves,  the  motor 
nerves  of  the  small  intestines,  for  Oliver  found  that  in  animals 
dead  from  lead-poisoning  the  small  intestines  were  contracted 
tightly  at  irregular  intervals,  and  Hertz  noted  by  the  #-rays  that 
the  retardation  occurs  in  the  small  intestine,  which  is  unusual  in 
constipation.  It  is  presumably  a  spastic  constipation.  Vaguez 
(1904)  and  Pal  (1905)  found  the  colic  associated  with  a  crisis  of 
general  arterial  hypertension.  Its  severity  can  be  lessened  by 
atropine,  by  opium,  or  by  cathartics,  the  establishment  of  coor- 
dinated peristalsis  apparently  aiding  in  overcoming  the  spasms. 
Colic  is  the  most  frequently  observed  of  the  striking  manifesta- 
tions. It  is  sometimes  followed  by  a  soreness  in  the  abdomen 
which  persists  for  weeks. 

2.  Palsy. — The  usual  lesion  is  a  motor  neuritis  of  the  musculo- 


LEAD 


491 


spiral  nerve  below  the  origin  of  the  branch  which  goes  to  the  sup- 
inator longus.  This  causes  paralysis  of  the  extensors  of  the  fore- 
arm, with  the  exception  of  the  supinator  longus,  and  shows  in  the 
characteristic  "wrist-drop."  The  first  paralysis  may  show  in  the 
extensor  indicis  and  the  extensor  minimi  digiti ;  the  extensor  meta- 
carpi  pollicis  usually  escapes.  The  intrinsic  muscles  of  the  hand 
undergo  considerable  atrophy.  The  paralyzed  muscles  show  the 
reaction  of  degeneration.  There  is  no  pain.  Though  this  is  the 
usual  lesion,  the  motor  neuritis  may  show  in  other  regions  also. 
Starr  says  that  colic  precedes  the  palsy  in  over  90  per  cent,  of  the 
paralytic  cases. 

There  may  also  be  a  general  peripheral  neuritis  (sensory 
and  motor)  similar  to  that  from  alcohol,  with  pain  or  great 
sensitiveness  to  pressure,  ataxia,  foot-drop,  etc.  It  may  be  so 
pronounced  as  superficially  to  resemble  locomotor  ataxia.  And 
there  may  be  an  optic  neuritis,  causing  temporary  or  permanent 
blindness,  or  involvement  of  any  of  the  cranial  nerves. 

3.  Encephalopathy. — This  is  a  rare  manifestation,  and  is  said 
to  be  more  frequent  in  negroes  than  in  whites.  It  may  give 
many  different  symptoms.  Intense  headache,  vertigo,  mental 
depression,  and  insomnia  are  the  most  common.  But  it  may  go 
on  to  violent  delirium,  with  convulsions  or  apoplexy,  or  may 
develop  into  dementia  paralytica.  Kehrer  says  that  lead  menin- 
gitis should  be  distinguished  from  lead  encephalopathy,  in  the 
latter  the  lesion  being  a  degeneration  of  the  vasa  vasorum  of  the 
brain  vessels. 

In  addition  to  these  striking  results,  the  continued  absorp- 
tion of  lead  is  believed  to  be  a  cause  of  arteriosclerosis,  of  chronic 
interstitial  nephritis,  of  gouty  attacks  (by  checking  the  elimina- 
tion  of  uric  acid).  In  female  workers  in  lead  it  has  frequently 
brought  on  abortion  by  causing  the  death  of  the  fetus.  Both 
diachylon  plaster  and  lead  pills  have  been  taken  to  produce 
abortion. 

After  death  from  lead'  there  is  a  striking  rapidity  of  decom- 
position with  putrefactive  odor.  The  largest  amount  of  lead  is 
found  in  the  liver. 

Diagnosis. — In  a  painter,  plumber,  or  other  worker  in  lead, 
anemia,  poor  nutrition,  a  bad  taste  in  the  mouth,  and  loss  of 
appetite  for  breakfast  are  always  suspicious  symptoms;  and  it  is 
highly  advantageous  for  the  patient  if  the  diagnosis  is  made  at 
this  stage.  In  one  not  known  to  be  working  in  lead,  the  cause 
may  not  be  suspected  until  the  characteristic  colic  or  palsy  makes 
its  appearance. 

In  a  well-marked  case  there  are  three  things  to  be  looked  for, 
viz.,  lead  in  feces  or  urine,  degenerated  red  cells,  and  a  lead  line 
on  the  gums.    Lead  is  frequently  but  not  always  found  in  the 


492  PHARMACOLOGY   AND   THERAPEUTICS 

feces  and  sometimes  in  the  urine.  Degenerative  stippling  or 
polychromatophilia  in  the  red  cells  was  found  by  Oliver  in  60 
per  cent,  of  cases.  It  is  probably  a  rather  late  manifestation, 
for  Rambousek  found  it  in  only  one  of  seven  animals  experi- 
mentally poisoned  with  lead  acetate. 

The  lead  line  on  the  gums  is  usual,  especially  if  the  teeth  are 
not  in  good  condition.  It  is  made  by  a  bluish  patch  just  below 
the  margin  of  each  gum,  and  is  usually  more  prominent  on  the 
lower  gums.  Occasionally  there  are  bluish-black  patches  on 
the  insides  of  the  cheeks  and  lower  lip.  If  the  teeth  are  absent, 
there  is  no  lead  line. 

Treatment.— As  prophylactic  measures,  lemonade  containing 
sulphuric  acid,  keeping  the  ringers  out  of  the  mouth  and  washing 
the  hands  before  eating,  and  proper  ventilation  to  remove  the 
dust  of  lead  salts  have  proved  extremely  efficient  in  Germany 
and  England. 

Potassium  iodide  is  the  usual  remedy,  but  in  experimental 
animals  Oliver  found  that  it  did  not  increase  the  elimination  of 
lead.  It  may  be  that  potassium  iodide  acts  to  overcome  the  high 
arterial  tension,  rather  than  to  promote  elimination.  Oliver 
recommends  milk  in  large  quantities  with  the  addition  of  sulphur, 
to  form  the  unabsorbable  lead  sulphide,  and  attention  to  the 
bowels.  The  use  of  sulphates  to  form  lead  sulphate  in  the  ali- 
mentary tract  has  been  recommended  on  the  mistaken  idea  that 
this  salt  is  not  absorbed. 

For  the  colic,  cathartics  are  indicated,  also  atropine,  warm 
baths,  heat  to  the  abdomen,  and,  in  some  cases,  opiates.  For 
the  neuritis  or  palsy  and  for  the  meningitis  the  usual  treatment 
for  such  conditions  is  called  for.  For  the  encephalopathy,  an 
ice-bag  to  the  head,  amyl  nitrite,  and  lumbar  puncture  may  be 
employed. 

COPPER 

Copper  (cuprum)  and  its  salts  have  a  peculiarly  deleterious 
action  upon  the  lower  forms  of  plant  life,  a  mere  trace  in  water, 
as  from  dragging  bags  of  copper  sulphate  through  the  water, 
being  found  sufficient  to  keep  it  free  from  algal  growth  without 
injuring  the  higher  plant  life  or  the  animal  life.  Even  contami- 
nated water  left  in  a  copper  vessel  will  after  a  time  be  found 
aseptic.  But  Clark  and  Gage  warn  against  the  assumption  that 
the  water  will  be  freed  from  bacteria  in  any  reasonable  length  of 
time,  and  they  find  that  vessels  made  of  other  metals  will  be 
just  as  effective  as  copper.  Pennington  and  associates  claim 
that  1  part  of  copper  sulphate  in  2,000,000  will  kill  typhoid  bacilli 
in  ten  hours;  but  Clark  and  Gage  find  that  even  1  in  100,000  kills 


ZINC 


493 


them  only  occasionally,  and  that  copper  sulphate,  to  be  safe, 
must  be  present  in  as  much  as  i  part  in  iooo. 

The  salt  regularly  employed  in  medicine  is  the  sulphate  or 
blue-stone.  It  is  locally  astringent,  irritating,  and  even  caustic. 
Its  taste  is  harsh  and  strongly  metallic,  and  when  it  is  swallowed, 
it  irritates  the  stomach  and  causes  vomiting. 

Uses. — Sticks  made  of  copper  sulphate  are  used  as  an  astrin- 
gent and  caustic  for  exuberant  granulations  and  granulated 
eyelids.  A  solution  of  5  to  15  grains  in  an  ounce  is  used  locally 
in  conjunctivitis,  urethritis,  and  vaginitis.  Ten  grains  (0.7  gm.) 
in  solution  have  been  used  as  an  emetic,  but  if  it  is  not  promptly 
vomited  it  may  injure  the  stomach.  Bevan  recommends  it  in 
dose  of  }/^  to  1  grain  (0.015-0.06  gm.)  in  actinomycosis. 

Toxicology. — Acute  poisoning  is  that  of  an  irritant,  and  is 
usually  checked  by  the  prompt  vomiting  of  the  drug.  Chronic 
poisoning  occurs  especially  in  brass  workers,  the  symptoms 
resembling  those  of  poisoning  by  other  metals.  Even  the  minute 
amounts  used  to  color  canned  vegetables  may  be  deleterious. 

ZINC 

The  zinc  (zincum)  salts  fall  into  two  distinct  classes,  viz.,  those 
which  are  irritant  locally  and  those  which  are  soothing  locally. 

The  irritant  salts  are  the  sulphate  and  the  chloride.  Their 
action  resembles  that  of  copper  sulphate.  The  sulphate  is  em- 
ployed in  1  to  5  per  cent,  solution  in  urethritis,  vaginitis,  and 
conjunctivitis.  To  produce  vomiting  the  dose  is  30  grains  (2  gm.) . 
The  chloride  is  also  caustic,  but  its  chief  use  is  in  1  per  cent, 
solution  as  an  odorless  disinfectant. 

The  soothing  salts  are  the  stearale,  which  is  a  light,  fluffy, 
rather  greasy,  white  powder,  and  the  oxide  and  carbonate,  which 
are  heavy  white  powders.  They  are  insoluble  in  water  and  very 
slightly  astringent,  and  are  of  value  as  soothing  protectives  to 
inflamed  surfaces.  They  may  be  employed  in  lotion  or  oint- 
ment form,  or  as  dusting-powders  in  chafed  or  inflamed  skin,  as 
in  eczema  or  dermatitis.  They  are  rarely  used  internally,  as 
they  tend  to  form  the  irritant  chloride. 

Zinc  ointment,  a  20  per  cent,  admixture  with  benzoinated 
lard,  is  very  widely  employed,  either  by  itself  or  as  a  vehicle 
for  other  drugs  in  the  treatment  of  the  skin.  Calamine,  a  natural 
impure  carbonate  of  zinc,  is  red  from  the  presence  of  iron,  and 
sometimes  slightly  gritty.  The  official  precipitated  carbonate 
of  zinc,  which  is  white,  is  a  pure  form.  Calamine  lotion  (un- 
official) is  a  mixture  of  zinc  oxide,  calamine,  glycerin,  lime-water, 
and  rose-water. 

The  oxide  and  the  sulphate  in  2-grain  (0.15  gm.)  doses  were 


494  PHARMACOLOGY  AND  THERAPEUTICS 

at  one  time  employed  in  epilepsy,  chorea,  whooping-cough, 
and  other  spasmodic  nervous  affections,  but  are  scarcely  used 
internally  at  present. 

BISMUTH 

The  bismuth  (bismuthum)  salts  commonly  employed  are  the 
subcarbonate  and  the  subnitrate,  which  are  white,  and  the  sub- 
gallate,  which  is  yellow.  Dose,  30  grains  (2  gm.).  They  are 
insoluble  in  water,  are  very  slightly  astringent,  and  resemble  in 
their  action  the  soothing  salts  of  zinc.  But  their  chief  use  is  in 
the  alimentary  tract,  where  they  do  not  form  irritant  compounds. 

They  act  in  a  purely  mechanical  manner  as  protectives  and 
demulcents  to  the  mucous  membrane  of  both  stomach  and  bowels. 
It  has  been  ascertained  that  if  given  before  irritant  emetics, 
they  can  prevent  vomiting.  The  author  has  in  a  number  of 
instances  given  bismuth  subnitrate  with  a  test-breakfast,  and 
has  usually  at  the  end  of  the  hour  found  a  much  lessened  secre- 
tion or  acidity.  In  a  few  cases  the  gastric  secretion  was  not 
changed  by  the  bismuth.  It  is  noteworthy  that  at  the  end  of 
the  test-breakfast  hour  the  bismuth  salt  was  uniformly  mixed 
with  the  extracted  stomach  contents,  and  that  it  had  changed 
from  a  heavy  powder  to  a  flocculent  substance  that  settled  slowly 
with  the  food.  Several  hours  after  its  administration  to  dogs 
the  author  found  the  bismuth  subnitrate  in  this  same  flocculent 
state,  and  coating  the  mucous  membrane  very  uniformly  as 
far  as  the  ileocecal  valve.  In  the  colon  the  bismuth  salt  becomes 
black  from  the  formation  of  the  sulphide,  and  this  renders  the 
stools  black.  As  the  sulphide  forms  hard  crystals,  it  sometimes 
acts  as  an  irritant. 

The  bismuth  salts  have  come  into  very  extensive  use  in 
x-ray  work,  their  opacity  to  the  rays  making  it  easy  to  obtain 
pictures  of  the  whole  alimentary  tract.  The  subcarbonate,  the 
oxide,  and  the  oxy chloride  are  employed  for  this  purpose  by 
mouth  or  rectum,  in  amounts  of  about  two  ounces,  mixed  with 
zoolak,  buttermilk,  thick  soup,  etc.  The  subnitrate  is  no  longer 
employed  in  these  large  amounts,  as  a  number  of  cases  of  bis- 
muth and  nitrite  poisoning  have  occurred  from  its  use. 

In  one  x-ray  case  of  the  author's  two  very  large  bismuth  balls 
formed  in  the  colon  and  had  to  be  broken  up  in  the  rectum  before 
they  could  be  extracted. 

Toxicology. — From  the  local  application  to  extensive  burns, 
from  the  injection  into  tuberculous  sinuses,  and  from  the  use  of 
it  for  x-ray  pictures,  bismuth  has  been  the  cause  of  poisoning. 
Its  symptoms  resemble  largely  those  of  poisoning  by  the  other 
heavy  metals,  and  are:    salivation  and  stomatitis,  with  a  black 


CERIUM  495 

or  blue-gray  line  on  the  gums,  nausea,  vomiting,  diarrhea,  signs 
of  kidney  and  colon  irritation,  and  collapse.  The  drug  is  mostly 
excreted  in  the  large  intestine.  Davis  and  Kaufmann  (1910) 
report  a  black  line  on  the  gums  in  6  out  of  25  cases  in  which 
bismuth  had  been  injected  into  tuberculous  sinuses  or  joints. 
One  fatal  case  occurred  from  less  than  one  ounce  of  the  33  per 
cent,  paste.  For  such  poisoning  Beck,  who  was  the  originator 
of  the  bismuth  treatment  for  sinuses,  recommends  to  flood  the 
sinus  or  cavity  with  warm  olive  oil  and  let  it  remain  for  twenty- 
four  hours,  and  to  wash  the  sinus  with  olive  oil  daily  thereafter 
until  the  symptoms  have  subsided.  He  advises  that  the  gums 
should  be  watched  for  the  blue  or  black  line,  which  is  the  first 
sign  of  poisoning. 

Therapeutics. — Beck's  method  of  treatment  of  chronic  sinuses 
or  tuberculous  cavities  is  to  inject,  not  oftener  than  once  a  week, 
a  33  per  cent,  paste  of  bismuth  subnitrate  with  vaseline.  He 
advises  against  it  in  acute  cases. 

Internally,  the  insoluble  bismuth  salts  are  used:  (1)  To 
check  nausea,  vomiting,  and  gastric  irritation,  as  in  ulcer  and 
marked  hyperchlorhydria.  (2)  To  check  intestinal  irritation, 
either  that  of  fermentative  diarrhea  or  that  from  inflammation 
of  small  intestine  or  colon.  The  soluble  bismuth  salts,  such  as 
the  citrate,  have  no  value  in  medicine  unless  the  bismuth  is  pre- 
cipitated from  them  in  the  alimentary  tract. 

Of  the  "milk  of  bismuth,"  a  white  suspension,  Hulse  (1910) 
reports  that  in  21  infants  with  gastro-enteritis  it  passed  through 
the  alimentary  tract  unchanged  and  without  effect;  while  inside 
of  twenty-four  hours  bismuth  subnitrate  resulted  in  diminished 
blood  and  mucus  and  fewer  stools,  and  showed  by  the  dark 
color  of  the  stools  that  it  had  undergone  change. 

CERIUM 

The  official  salt  of  cerium  (cerium)  is  the  oxalate,  Ce2(C204)2.- 
ioH20,  an  inert  powder,  insoluble  in  water.  The  commercial 
article  is  very  impure.  Its  action  is  practically  that  of  the  in- 
soluble bismuth  salts  in  allaying  gastric  and  intestinal  irrita- 
tion, but  its  therapeutic  use  is  mostly  to  check  nausea  and 
vomiting.  Baehr  and  Wessler  (1909)  found  it  non-poisonous  to 
dogs  even  in  doses  of  50  grams  (1  %  oz.).  They  noted  also  that 
its  action  was  mechanical  as  a  protective  to  the  gastric  mucous 
membrane,  and  that  it  would  check  the  vomiting  from  stomach 
irritants;  but  that  it  had  no  influence  on  the  vomiting  brought 
about  by  apomorphine,  which  is  a  central  emetic.  They  found 
the  usual  dose  entirely  too  small  for  protective  purposes,  and 
recommend  doses  of  30  to  60  grains  (2-4  gm.).     A  mixture  of 


496  PHARMACOLOGY  AND  THERAPEUTICS 

cerium  oxalate,  5  grains  (0.3  gm.),  and  sodium  bicarbonate, 
10  grains  (0.7  gm.),  has  frequently  been  employed  in  refractory 
cases  of  nausea  and  vomiting,  as  in  pregnancy;  but  it  is  probable 
that  any  good  effect  from  such  small  amounts  has  been  due  to 
the  sodium  bicarbonate. 

SILVER  (ARGENTUM) 

The  official  salt  employed  is  silver  nitrate,  a  crystalline  salt 
which  is  decomposed  by  oxidizable  organic  matter  and  light, 
and  is  soluble  in  less  than  its  own  weight  of  water.  "Lunar 
caustic"  is  silver  nitrate  toughened  by  the  addition  of  hydro- 
chloric acid  to  make  a  small  amount  of  silver  chloride  (horn 
silver),  and  molded  into  sticks. 

Silver  nitrate  is  antiseptic  and  very  irritant  locally.  It 
coagulates  protein,  so  is  astringent,  and  may  readily  destroy 
the  soft  tissues,  so  is  caustic.  It  has  little  penetrating  power, 
and  its  action  may  be  checked  very  promptly  by  sodium  chloride, 
which  changes  it  to  the  inert  silver  chloride.  Wildbolz  (1907), 
by  reduction  with  the  Finsen  light,  found  that  1:1000  to  1:100 
solutions  penetrated  to  the  subepithelial  tissue  of  a  dog's  urethra, 
while  1  to  3  per  cent,  solutions  of  protargol  had  less  penetrating 
power. 

In  2  per  cent,  solution  silver  nitrate  is  used  as  a  prophylactic 
against  gonorrheal  ophthalmia  in  the  new-born  (Crede's  method). 
In  0.5  to  5  per  cent,  solution  it  is  employed  in  nose  and  throat, 
or  for  cracked  nipples  or  canker  sores  or  ulcers,  and  in  0.5  to  1 
per  cent,  solution  for  the  urethra,  conjunctiva,  vagina,  or  bladder 
in  various  infections. 

The  lunar  caustic  is  employed  to  destroy  exuberant  granu- 
lations, to  remove  small  neoplasms,  warts,  condylomata,  etc., 
and  to  stimulate  the  surface  of  a  sluggish  ulcer  or  sore.  To  re- 
move a  wart  the  pointed  caustic  stick  is  moistened  and  bored 
down  into  the  central  artery  of  the  wart.  The  wart  turns  black 
and  may  be  removed  in  a  few  days. 

In  the  stomach,  the  nitrate  has  been  employed  in  hyper- 
chlorhydria  and  chronic  gastritis;  but  as  it  is  immediately 
rendered  inert  by  hydrochloric  acid  or  sodium  chloride,  it  is 
useless  unless  preceded  by  thorough  lavage.  If  it  is  employed 
at  all,  the  best  method  is  to  administer  it  in  1:500  solution 
through  the  lavage  tube,  and  then,  after  two  or  three  minutes, 
to  remove  it  by  thorough  lavage.  If  it  is  desired  to  give  silver 
nitrate  in  pills,  kaolin  and  petrolatum  should  be  employed  in 
their  manufacture,  for  extracts,  glucose,  glycerin,  and  other 
organic  excipients  will  render  the  nitrate  inert. 

The  nitrate  makes  a  black  stain  on  exposure  to  light,  to 


SILVER    (ARGENTUM) 


497 


remove  which  the  skin  ma)*  be  washed  with  solution  of  potassium 
cyanide,  or  covered  with  tincture  of  iodine  and  washed  off  with 
solution  of  sodium  hyposulphite. 

A  number  of  organic  silver  compounds  are  also  to  be  had, 
the  most  used  of  which  are  argyrol  (silver  vitellin)  and  protargol 
(silver  protein).  Colloidal  silver,  collargol,  is  also  employed 
by  mouth  in  dose  of  45  grains  (3  gm.),  by  inunction  with  a 
15  per  cent,  ointment,  and  intravenously  for  septic  conditions 
in  doses  of  2  drams  (8  c.c.)  of  a  2  per  cent,  solution.  These 
preparations  are  not  essentially  astringent,  and  are  not  pre- 
cipitated by  albumin  and  chlorides.  As  argyrol  and  collargol 
are  non-irritant,  and  protargol  only  slightly  irritant,  they  have 
come  into  very  extensive  use  to  replace  silver  nitrate.  But 
comparative  studies  of  the  relative  antiseptic  values  of  the  silver 
preparations  show  that  the  only  one  with  pronounced  germicidal 
effect  is  the  silver  nitrate.  Albuminous  substances,  as  in  serum 
and  the  tissues,  quickly  destroy  the  antiseptic  power.  Marshall 
and  Neave  have  shown  that  the  percentage  of  silver  does  not 
indicate  the  antiseptic  value. 

Derby  (1906)  tested  a  staphylococcus  on  a  mixture  of  hydro- 
cele fluid  and  bovine  serum.  With  an  equal  volume  of  2  per 
cent,  silver  nitrate  he  could  still  obtain  a  growth  after  30  to  40 
minutes;  with  an  equal  volume  of  8  per  cent,  protargol,  a  growth 
after  sixty  minutes;  and  with  50  per  cent,  argyrol,  an  abundant 
growth  after  three  and  one-half  hours. 

Bayard  Clark  and  Wylie  (191 1)  report  an  extensive  series 
of  comparative  bacteriologic  studies,  from  which  we  take  the 
following  as  examples: 


Number 

of  Colonies  from  One 

LOOPFUL   TAKEN   AFTER 

Organism 

Solution 

S  minutes 

15  minutes 

30  minutes 

Streptococcus.  .  . 

2  per  cent,  silver  nitrate .  . 

O 

O 

O 

1  per  cent,  silver  nitrate .  . 

6 

5 

O 

10  per  cent,  protargol 

25 

20 

20 

30  per  cent,  argyrol 

0 

0 

O 

10  per  cent,  argyrol 

4 

0 

O 

2.5  per  cent,  collargol 

15 

8 

O 

Gonococcus 

1  :  5000  silver  nitrate 

0 

0 

0 

1  :  1000  silver  nitrate 

0 

0 

O 

10  per  cent,  protargol 

3° 

25 

15 

30  per  cent,  argyrol 

70 

5° 

IO 

2.5  per  cent,  collargol  .... 

80 

100 

15 

32 


498  PHARMACOLOGY  AND  THERAPEUTICS 

These  might  be  compared  with  the  table  given  under  Disin- 
fectants. 

Untoward  effects  of  silver  are:  (i)  argyria,  a  bluish  staining  of 
the  skin  which  is  permanent.  It  may  appear  in  spots  (the 
"spotted  boy"  of  the  circus).  It  usually  was  the  result  of  the 
now  obsolete  treatment  of  epilepsy  and  other  nervous  diseases 
with  silver  nitrate. 

(2)  There  is  also  at  times  from  the  local  use  in  the  eye  a  con- 
junctival argyria.  According  to  Theobald,  this  is  more  common 
from  the  organic  compounds  than  from  the  nitrate. 

Collargol  and  argyrol  solutions  are  employed  for  injection 
into  the  ureters  to  obtain  #-ray  pictures  of  the  ureter  and  kidney 
pelvis. 

ALUMINIUM  (ALUMINUM) 

Alum  (alumen,  aluminis)  of  the  Pharmacopoeia  is  potassium 
alum,  the  double  sulphate  of  aluminium  and  potassium,  K2A12- 
(S04)4.24H20.  It  is  soluble  in  9  parts  of  water  and  insoluble 
in  alcohol.  Its  taste  is  sour,  and  it  is  decidedly  astringent  by 
coagulation  of  the  proteins  of  the  superficial  cells,  but  it  is  not 
very  irritant.  It  is  a  constituent  of  some  baking-powders,  but 
is,  without  much  doubt,  harmful  to  digestion. 

It  is  employed,  usually  in  5  per  cent,  solution,  as  a  gargle 
or  spray  in  relaxed  sore  throat,  as  a  vaginal  douche,  and  as  a  wash 
for  the  skin  to  stop  local  sweating  of  the  hands  and  feet  or  the 
night-sweats  of  tuberculosis.  The  crystals  may  be  used  to 
shrink  canker  sores  in  the  mouth,  or  to  check  hemorrhage 
from  scratches  or  small  cuts.  The  powdered  alum  has  been  used 
in  60-grain  (4  gm.)  dose  as  an  emetic,  but  is  not  at  all  reliable. 

Burnt  alum  (alumen  exsiccatum)  is  alum  with  the  water  of 
crystallization  driven  off  by  heat.  It  has  a  great  affinity 
for  water,  is  powerfully  astringent,  and  is  slightly  caustic.  Its 
chief  employment  is  as  an  application  to  sluggish  ulcers. 

The  solution  of  aluminium  acetate,  N.  F.  (Burow's  solution), 
is  made  by  acting  on  calcium  acetate  with  aluminium  sulphate 
in  solution,  the  insoluble  calcium  sulphate  being  removed  by 
filtration.  It  is  sometimes  prepared  by  mixing  solutions  of  alum 
and  lead  acetate,  the  lead  sulphate  formed  being  filtered  off. 
Poisoning  has  occurred  from  failure  to  remove  the  precipitated 
lead  salt.  It  is  a  slightly  astringent,  slightly  antiseptic  liquid, 
the  chief  use  of  which  is  as  a  wet  dressing  for  infected  wounds. 
Koll  (191 2)  reports  great  success  with  it  in  42  cases  of  colon- 
bacillus  infection  of  the  urinary  tract. 


iron  499 


IRON 

There  are  many  official  preparations  of  iron  (ferrum),  but 
a  knowledge  of  only  seven  or  eight  will  give  a  good  equipment 
for  iron  therapy.  (Those  made  in  our  laboratory  were  the  syrup 
of  ferrous  iodide,  the  solution  of  ferric  chloride,  the  tincture  of 
ferric  chloride  the  liquor  ferri  et  ammonii  acetatis,  Blaud's  pills 
of  ferrous  carbonate,  and  the  arsenic  antidote  of  ferric  hydroxide 

with  magnesia.) 

There  are  four  main  uses  in  medicine  for  preparations  of 

iron,  as  follows:  . 

i    Disinfectant— Ferrous  sulphate  (copperas) ,  for  sinks,  water- 
closets,  cess-pools,  etc.    It  is  cheap,  but  not  very  effective. 

2  Astringent— The  ferrous  and  ferric  salts  of  the  mineral 
acids'  especially  the  sulphates,  the  subsulphates,  and  the  chlorides, 
precipitate  protein,  are  strongly  astringent,  and  coagulate  the 
blood  They  are  also  irritant.  A  mixture  of  equal  parts  of  the 
tincture  of  ferric  chloride,  glycerin,  and  water  is  a  favorite  appli- 
cation in  sore  throat;  it  is  astringent  and  irritant;  it  may  attack 
the  teeth  The  use  of  these  astringent  preparations  in  nose-bleed 
and  other  small  hemorrhages  (the  styptic  action)  results  ma 
dirty  coagulum  and  irritation  of  the  tissues,  and  it  has  practically 
been  abandoned.  Liquor  ferri  chloridi,  liquor  fern  subsidphatis 
(Monsel's  solution),  and  liquor  ferri  tersulphatis  are  official. 

3  Arsenic  Antidote.— The  freshly  precipitated  ferric  hydrox- 
ide changes  the  active  arsenous  preparations  into  the  compara- 
tively inactive  and  insoluble  arsenic  compounds  of  iron.  Amy 
gives  the  reaction  with  arsenous  acid  as:  3AS2O3  +  2Fe(OH)3  - 

2Fe(As02)3  +  3H2O.  .  . 

Ferric  hydroxide  (ferri  hydroxidum)  is  made  by  precipi- 
tating the  solution  of  ferric  sulphate  with  ammoma  water, 
filtering,  and  washing  the  precipitate  with  water  to  remove  the 
ammonium  sulphate.  It  may  be  made  just  as  well  from  the 
solution  or  tincture  of  ferric  chloride.  Fern  hydroxidum  cum 
magnesii  oxido  is  made  with  a  mixture  of  magnesium  oxide  and 
water  instead  of  ammonia  water, 

MgO  +  H20  =  Mg(OH)2 
Fe2(S04)3  +  3Mg(OH)2  =  2Fe(OH)3  +  3MgS04 

It  is  not  necessary  to  wash  out  the  magnesium  sulphate. 
Ferric  hydroxide  as  an  antidote  may  be  administered  111  large 
quantity,  after  which  it  must  be  washed  out  of  the  stomach  witn- 

°Ut4  eHematinic,  tending  to  increase  the  hemoglobin  content  of 
the  blood.    The  hematinics  may  be  separated  into  six  varieties: 


500  PHARMACOLOGY   AND   THERAPEUTICS 

(a)  Metallic  Iron  (Ferrum  Reductum;  Reduced  Iron). — Dose, 
i  grain  (0.06  gm.).  It  is  a  fine,  grayish-black  powder,  made  by 
reducing  ferric  oxide  with  hydrogen.  It  consists  of  not  less  than 
90  per  cent,  pure  iron,  and  requires  acid  in  the  stomach  for  its 
solution. 

(b)  The  Inorganic  Ferrous  Salts. — They  are:  The  carbonate 
in  the  saccharated  carbonate,  massa  ferri  carbonatis  (Vallet's 
mass),  and  pilula  ferri  carbonatis  (Blaud's  pills);  the  iodide  in 
pills  of  ferrous  iodide  and  syrup  of  ferrous  iodide,  dose,  30  minims 
(2  c.c);  the  sulphate,  dose,  3  grains  (0.2  gm.);  the  dried  sulphate, 
dose,  2  grains  (0.13  gm.) ;  the  latter  in  pills  of  aloes  and  iron,  each 
containing  1  grain  (0.06  gm.). 

(c)  The  Inorganic  Ferric  Salts. — They  are:  The  chloride, 
dose  of  the  tincture,  5  minims  (0.3  c.c);  the  hypo  phosphite, 
phosphate,  and  pyrophosphate,  dose  of  each,  4  grains  (0.25  gm.); 
the  elixir  and  the  syrup  of  the  phosphates  of  iron,  quinine,  and 
strychnine,  dose,  2  drams  (8  c.c).  The  hypophosphite  is  present 
in  the  "compound  syrup  of  the  hypophosphites. "  These  mineral 
salts  are  astringent,  irritating  to  the  stomach,  and  constipating. 
In  liquid  form  they  tend  to  blacken  the  teeth  and  to  injure  the 
enamel.  To  protect  the  teeth  the  dose  should  be  well  diluted, 
taken  through  a  tube,  and  followed  by  rinsing  the  mouth.  The 
tincture  of  the  chloride  contains  free  acid  and  is  especially 
destructive  to  the  teeth. 

(d)  The  Salts  of  Organic  Acids. — These  are  the  ferric  acetate, 
citrate,  and  tartrate.  Favorite  preparations  are:  Liquor  ferri 
et  amnwnii  acctatis  (Basham's  mixture),  dose,  2  drams  (8 c.c); 
and  the  soluble  double  alkaline  salts,  iron  and  ammonium  citrate, 
iron  and  ammonium  tartrate,  and  iron  and  potassium  tartrate, 
dose,  4  grains  (0.25  gm.).  The  citrate  of  iron  and  quinine,  dose, 
4  grains  (0.25  gm.),  containing  x/2  grain  of  quinine,  and  the 
citrate  of  iron  and  strychnine,  containing  1  per  cent,  of  strych- 
nine, dose,  2  grains  (0.13  gm.),  are  also  official.  There  are  two 
official  wines,  vinum  ferri,  containing  4  per  cent,  of  iron  and 
ammonium  citrate,  and  the  bitter  wine  of  iron,  vinum  ferri 
amarum,  containing  5  per  cent,  of  iron  and  quinine  citrate,  each 
preparation  being  made  with  tincture  of  sweet  orange  peel,  syrup, 
and  white  wine. 

The  salts  of  this  group  do  not  readily  dissociate,  so  they  do 
not  readily  precipitate  proteins.  Hence  they  are  less  irritant, 
less  astringent,  and  less  constipating  than  the  salts  of  the  mineral 
acids.    Their  solutions  do  not  corrode  the  enamel  of  the  teeth. 

The  citrate  in  5  per  cent,  solution  has  been  used  hypoder- 
matically  in  dose  of  1  grain  (0.06  gm.)  with  reported  rapid  effects. 

(e)  Artificial  Protein  (or  Organic)  Compounds. — Albuminates, 


IRON  50I 

peptonates,  etc.  Ovoferrin  is  a  liquid  purporting  to  be  made  from 
the  white  of  egg;  ferratin,  a  preparation  claimed  incorrectly 
to  be  the  natural  iron  compound  of  the  pig's  liver. 

(/)  True  "organic"  or  "masked"  iron,  sometimes  spoken  of 
as  food  iron,  as  in  hemoglobin  or  yolk  of  egg. 

Absorption.— To  prevent  irritation  of  the  stomach,  iron  prep- 
arations are  regularly  administered  after  meals,  and  mostly  form 
the  ferrous  chloride  or  albuminate  in  the  stomach.  On  passing  to 
the  duodenum,  the  chloride  or  sulphate  probably  changes  to  the 
carbonate.  After  a  meal  containing  an  added  iron  salt,  granules 
of  iron  are  found  in  the  epithelium  and  leukocytes  of  the  duodenal 
mucous  membrane  and  in  no  other  portion  of  the  alimentary  tract 
(Macallum).  But  after  an  iron-nuclein  compound,  Cloetta 
found  it  also  in  the  membrane  much  further  down  the  small  intes- 
tine. It  enters  the  blood  probably  either  as  the  albuminate  or 
carbonate.  There  seems  to  be  no  essential  difference  in  absorb- 
ability between  the  inorganic  and  organic  forms  of  iron. 

A  medicinal  dose  of  an  iron  salt  is  3  to  5  grains,  but,  as  has 
been  shown  by  severing  the  intestine  above  the  cecum,  almost  all 
of  this  passes  through  the  alimentary  tract  unabsorbed.  Some  of 
it  forms  the  sulphide,  and  this  may  give  a  dark  or  blackish  color 
to  the  feces.  Charteris  found  that  }4  to  1  grain  (0.03-0.06  gm.) 
daily  by  hypodermatic  of  an  albuminate  of  iron  given  to  rabbits 
for  over  a  month  had  no  especial  effect.  They  maintained  health, 
and  their  marrow  was  only  slightly,  if  at  all,  increased  in  density 
or  vascularity.  But  healthy  mice  fed  on  cheese  and  iron  regularly 
contained  more  iron  in  their  tissues  than  control  mice  fed  on 
cheese  alone,  and  healthy  goats  fed  on  milk  and  iron  more  than 
goats  fed  on  milk  alone.  Iron  that  is  absorbed  but  does  not  enter 
into  hemoglobin  or  some  other  natural  organic  compound  is  a 
foreign  substance  and  is  poisonous. 

The  Absorbed  Iron.— This  passes  into  the  portal  blood  and 
perhaps  slightly  into  the  lymph,  and  is  soon  found  deposited  in 
the  spleen  and  mesenteric  lymph-nodes  and  slightly  in  the  liver- 
cells  and  the  cells  of  the  convoluted  tubules  of  the  kidney.  Later 
it  is  found  in  greatest  abundance  in  the  bone-marrow  and  liver, 
and  still  later  appears  in  the  epithelium  of  the  colon  and  rectum 
where  it  is  excreted  into  the  feces.  Of  the  iron  excreted  by  normal 
persons  under  normal  conditions,  about  nine-tenths  is  excreted  in 
the  feces,  and  one-tenth  in  the  urine.  Practically  all  the  medici- 
nal iron  is  excreted  in  the  feces.  A  portion  of  the  iron  ot  the 
liver  is  synthetized  into  organic  compounds  (ferratin,  etc.),  ready 
for  conversion  into  hemoglobin,  and  the  rest  is  doled  out  for  excre- 
tion There  is  no  increase  in  the  amount  of  iron  in  the  bile. 
Effect  on  Blood.— Normally,  the  whole  adult  human  body 


502  PHARMACOLOGY  AND  THERAPEUTICS 

contains  from  40  to  55  grains  of  iron,  enough  to  make  a  two-inch 
nail.  The  ordinary  diet  contains  tV  to  |  grain  (5  to  10  mg.)  of 
iron  per  day,  this  minute  amount  being  sufficient  to  maintain  the 
iron  equilibrium  of  the  body.  During  the  growing  period  more 
iron  is  necessary.  In  human  milk,  between  the  third  and  twelfth 
days  of  lactation,  Cameron  found  21  mg.  of  iron  in  100  c.c;  while 
in  mixed  cow's  milk  Bunge  found  3.5  mg.,  and  Van  Slyke  only  1  mg. 
in  100  c.c.  Krasnogorsky  found  the  iron  of  milk  more  readily 
absorbed  than  that  of  egg-yolk  or  spinach. 

For  over  a  month  Charteris  (1903)  gave  normal  rabbits  a 
daily  hypodermatic  of  yi  to  1  grain  (0.03-0.06  gm.)  of  an  albu- 
minate of  iron.  They  maintained  health  and  gained  weight.  There 
was  no  essential  change  in  the  bone-marrow  except  a  slight 
increase  in  the  leukoblastic  elements.  Therefore,  in  health, 
though  the  administration  of  iron  results  in  some  accumulation 
of  iron  either  free  in  the  blood  or  stored  up  in  the  liver,  spleen, etc., 
it  is  not  followed  by  an  increase  in  either  the  hemoglobin  or  the 
red  cells,  and  the  iron  is  in  a  sense  a  foreign  body;  that  is,  it  does 
not  go  to  form  blood,  and  there  is  no  plethora  established.  But 
after  bleeding,  animals  have  been  shown  to  utilize  iron  that  was 
given  them,  and  in  many  human  cases  with  hemoglobin  below 
normal  its  administration  seems  to  be  followed  by  a  greater  in- 
crease in  both  the  hemoglobin  and  the  red  cells  than  comes  from 
the  food  alone.  In  these  cases  it  is  possible  that  "under  the 
stimulus  of  iron  the  blood-forming  organs  become  active  in  the 
synthesis  of  hemoglobin"  (von  Noorden). 

Hemoglobin  itself,  as  in  raw  blood  or  uncooked  meat,  is  con- 
verted by  the  gastric  juice  to  acid  hematin,  and  when  taken  by 
man  is  believed  to  be  mostly  unabsorbed.  It  has  been  ascertained 
that  1  c.c.  of  blood  by  mouth  will  give  a  test  in  the  feces.  How- 
ever, Halliburton 's  experiments  with  raw  blood  on  rats  fed  on  an 
otherwise  iron-poor  diet,  showed  a  slight  increase  in  the  red  blood- 
corpuscles  and  hemoglobin  of  the  blood,  and  the  presence  of 
absorbed  iron  in  the  cells  of  the  duodenal  mucous  membrane. 

In  cooked  blood,  as  in  cooked  meat,  the  hemoglobin  is  changed 
and  is  absorbed  more  readily,  but  even  then  not  readily. 

Toxicology. — In  excessive  amounts  iron  may  produce  nausea, 
vomiting,  constipation,  and  headache.  Dixon  says  that  if  it  is 
administered  intravenously  it  is  as  toxic  as  arsenic.  In  very  large 
quantities  the  irritant  inorganic  salts  may  cause  great  irritation 
of  stomach  and  bowels,  with  collapse.  There  is  no  satisfactory 
evidence  that  excess  of  iron  has  any  power  to  increase  a  hemor- 
rhagic tendency  or  to  bring  on  plethora. 

Therapeutics. — The  therapeutic  classification  given  above 
indicates  its  uses.    As  a  hematinic  it  may  be  employed  in  all  con- 


ARSENIC    (ARSENUM)  503 

ditions  with  diminished  hemoglobin.  Its  most  prompt  effects  are 
seen  in  chlorosis,  but  good  results  may  also  follow  its  use  in  the 
secondary  anemias.  It  is  best  given  in  conjunction  with  appe- 
tizers, tonics,  laxatives,  etc.,  according  to  need.  In  nephritis  the 
anemia  is  often  treated  with  iron,  especially  Basham's  mixture, 
but  there  is  no  satisfactory  evidence  of  any  direct  effect  upon  the 
kidneys  or  upon  the  excretion  of  albumin.  It  has  been  employed 
also  in  functional  albuminuria,  and  there  is  a  traditional  belief 
that  it  will  cure  this  condition.  The  citrate  has  been  used  hypoder- 
matically,  in  5  per  cent,  solution,  in  dose  of  0.05  gm.  daily.  It  is 
readily  absorbed. 

MANGANESE 

Though  found  in  the  tissues  in  minute  quantity,  manganese 
is  not  essential  to  life,  and  does  not  form  an  integral  part  of  any 
protein  molecule.  For  some  unexplained  reason,  however,  it  has 
been  used  more  or  less  in  anemia  in  combination  with  iron,  e.  g., 
in  the  form  of  a  peptonate  or  albuminate. 

Manganese  dioxide,  dose,  2  grains  (0.013  gm.),  and  potassium 
permanganate,  dose,  1  grain  (0.06  gm.),  are  official  and  have  a 
reputation  as  emmenagogues.  Potassium  permanganate,  through 
its  oxidizing  powers,  is  locally  antidotal  to  morphine,  and  in 
1 :  10,000  to  1 :  1000  aqueous  solution  has  considerable  value  as  an 
antiseptic  and  deodorizer.  It  has  been  found  useful  in  India 
locally  in  snake-bite,  and  is  recommended  by  von  Adelung  in  ivy- 
poisoning. 

Casamajor  (19 13)  reports  chronic  poisoning  in  workers  in 
zinc  mines,  and  Embden,  in  workers  about  a  manganese  dioxide 
grinding  mill.  Great  muscular  weakness,  a  coarse  intention 
tremor,  muffled  speech,  and  depressed  cerebration  were  the  most 
striking  features. 

ARSENIC    (ARSENUM) 

Arsenic  is  widely  distributed  in  nature  and  can  be  detected  in 
many  of  our  commonly  used  chemicals  and  even  in  certain  chemic 
drugs.  It  is  said  to  appear  in  the  fruit  of  trees  sprayed  with  Paris 
green,  and  in  other  plants  grown  in  the  soil  where  Paris  green 
has  been  used. 

Preparations  and  Doses. — (a)  Those  of  Arsenous  Acid. — 
Arsenic  trioxide,  arsenous  acid,  white  arsenic,  AS2O3,  is  an  anhy- 
dride which  occurs  as  a  practically  odorless  and  tasteless  white 
powder,  made  either  from  the  glassy  variety,  soluble  in  30  parts  of 
water,  or  from  the  porcelain  or  crystalline  variety,  soluble  in  100 
parts  of  water.  Both  dissolve  in  5  parts  of  glycerin  and  are 
sparingly  soluble  in  alcohol.     Dose,  ^  grain  (0.002  gm.). 


504  PHARMACOLOGY  AND  THERAPEUTICS 

Solution  of  arsenous  acid,  liquor  acidi  arsenosi,  1  per  cent.,  is 
acid  with  hydrochloric  acid.     Dose,  3  minims  (0.2  c.c). 

Fowler's  solution,  liquor  potassii  arsenitis,  KAsO2.HAsO9.H2O, 
1  per  cent.,  contains  the  compound  tincture  of  lavender  to  give  it 
distinctive  odor,  taste,  and  color  as  a  preventive  against  accidents. 
Dose,  3  minims  (0.2  c.c).  This  is  the  favorite  liquid  preparation. 
It  is  incompatible  with  acids,  and  tends  to  oxidize  and  deteriorate. 

Arsenic  iodide,  ASI3;   dose,  y1^-  grain  (0.005  gm.). 

Donovan's  solution,  liquor  arseni  et  hydrargyri  iodidi,  contains 

1  per  cent,  each  of  arsenous  iodide  and  mercuric  iodide.     Dose, 

2  minims  (0.12  c.c). 

(b)  Those  of  A  rsenic  A  cid. — Sodium  arsenate,  Na2HAs04 ,  ?H20 ; 
dose,  yV  grain  (0.005  gm.). 

Dried  sodium  arsenate,  sodii  arsenas  cxsiccahis,  is  sodium 
arsenate  deprived  of  its  water  of  crystallization  by  heat.  As  this 
water  constitutes  about  two-fifths  of  the  arsenate,  the  drying 
nearly  doubles  the  strength.    Dose,  -^V  grain  (0.003  gm.). 

Solution  of  sodium  arsenate,  1  per  cent,  of  the  dried  salt;  dose, 

3  minims  (0.2  c.c). 

(c)  Besides  the  official  preparations,  there  are  a  number  of 
organic  compounds  that  are  in  use: 

Sodium  arsanilate  (sodium  aminophenyl  arsonate)  is  employed 
in  the  form  of  atoxyl,  C6H4(NH2).(AsO.OH.ONa)  +  3H2O,  con- 
taining 3  molecules  of  water  of  crystallization  and  26  per  cent,  of 
arsenic;  and  soamin,  C6H4(NH2).(AsO.OH.ONa)  +  5H2O,  which 
contains  5  molecules  of  water  of  crystallization  and  22  per  cent, 
of  arsenic.  They  are  white  powders,  soluble  in  5  or  6  parts  of 
water,  and  decomposed  by  acids.  Because  of  the  acidity  of  the 
gastric  juice,  they  are  given  hypodermatically.  Dose,  ^3  to  3 
grains  (0.02-0.2  gm.)  every  second  day. 

Arsacetin  is  sodium  acetyl  arsanilate,  C6H4(NHCH3CO).- 
(AsO.OH.ONa),  soluble  in  10  parts  of  cold  water  and  3  parts  of 
hot  water.  It  can  be  sterilized  in  the  autoclave  at  1300  C.  for  one 
hour  without  decomposition.  The  claim  is  made  that  it  is  not 
split  up  by  acids.  The  hypodermatic  dose  is  3  grains  (0.2  gm.) 
two  or  three  times  a  week.  By  mouth  the  dose  is  ^  grain 
(0.05  gm.)  three  or  four  times  a  day. 

Arsenopkenylglycin,  As2(COOH.CH2.N.H.C6H4)2,  has  a  hypo- 
dermatic dose  of  12  grains  (0.8  gm.). 

Sodium  cacodylate,  the  sodium  salt  of  dimethyl  arsenic,  (CH3)2- 
AsO.ONa  +  3H2O,  is  readily  soluble  in  water.  It  liberates  arsenic 
quite  slowly,  hence  is  less  toxic  and  less  active  than  the  inorganic 
salts.  Dose,  1  grain  (0.06  gm.)  hypodermatically,  or  3  grains 
(0.2  gm.)  by  mouth  daily.  A  hypodermatic  of  4  to  6  grains 
(0.25-0.35  gm.),  repeated  in  four  days,  was  recommended  by  John 


ARSENIC    (ARSENUM)  505 

B.  Murphy  in  syphilis.  A  number  of  other  compounds  of  caco- 
dylic  acid  have  also  been  employed,  as  those  of  iron,  mercury, 
quinine,  lithium,  etc. 

Salvarsan,  Ehrlich's  "606,"  is  diamino-dihydroxy-arseno- 
benzol  dihydrochloride,  (C6H3As.OH.NH2HCl)2.  It  is  a  bright 
yellow  powder,  of  strongly  acid  reaction,  and  completely  but 
slowly  soluble  in  10  parts  of  water.  It  is  used  somewhat  hypoder- 
matically,  but  preferably  intravenously.  Before  use  it  must  be 
freshly  made  into  a  sterile  solution  of  slightly  alkaline  or  neutral 
reaction.  It  is  very  readily  oxidized,  so  is  kept  in  vacuo,  or  in 
ampules  filled  with  an  indifferent  gas.  The  dose  is  10  grains 
(0.6  gm.),  which  for  intravenous  use  is  dissolved  in  300  c.c.  of 
normal  saline  to  which  23  drops  of  15  per  cent,  sodium  hydroxide 
solution  are  added. 

Neo-salvarsan,  soluble  in  water  and  of  neutral  reaction,  may 
be  administered  with  much  greater  ease.  It  is  sodium-diamino- 
dihydroxy-arseno-benzol-methanal  sulphoxylate  mixed  with  half 
its  weight  of  inert  substance.  Dose,  10  grains  (0.6  gm.)  every 
second  day  for  four  days.  It  deteriorates  very  quickly,  so  must  be 
kept  in  vacuo.    It  is  increased  in  toxicity  by  saline  solution. 

Pharmacology. — Microorganisms. — Arsenic  is  added  to 
embalming  mixtures  to  prevent  rapid  decomposition.  It  is 
more  destructive,  however,  to  highly  organized  life  than  to 
bacteria. 

Local. — Arsenic  is  irritant.  It  does  not  precipitate  protoplasm 
and  does  not  form  an  albuminate,  but  slowly  acts  on  the  tissues 
to  produce  inflammation.  An  arsenic  paste,  for  example,  causes 
pain,  redness,  and  swelling,  with  fatty  degeneration  of  the  epithe- 
lium and  inflammation  of  the  tissues  beneath.  The  inflammatory 
reaction  may  be  so  intense  that  destruction  of  tissue  follows,  with 
sloughing  and  the  formation  of  an  ulcer.  The  drug  is,  therefore, 
a  slowly  acting  and  very  painful  caustic,  which  destroys  tissue, 
not  by  precipitating  protoplasm,  but  by  inducing  an  acute  inflam- 
matory reaction.  In  its  use  to  destroy  the  nerves  of  teeth  the 
destruction  of  the  nerve  depends  upon  inflammation  and  swell- 
ing in  the  opening  of  the  root  of  the  tooth,  so  that  the  circulation 
of  the  nerve  is  cut  off. 

Alimentary  Tract. — Nausea,  vomiting,  diarrhea,  and  colic  are 
commonly  seen  from  the  use  of  arsenic.  These  effects  seem  to  be 
produced  after  absorption,  for  they  occur  late,  and  even  when  the 
drug  is  administered  hypodermatically.  Experimentally,  after 
large  hypodermatic  injections,  there  is  edema  of  the  intestine  from 
increased  permeability  of  the  capillaries,  with  degeneration  and 
exfoliation  of  the  intestinal  epithelium.  Arsenic-eaters  claim 
that  it  helps  the  appetite. 


506  PHARMACOLOGY  AND  THERAPEUTICS 

Absorption  takes  place  from  the  stomach  with  fair  rapidity 
when  the  preparation  is  in  solution.  The  power  of  absorption 
may  be  rendered  less  by  repeated  doses.     (See  Tolerance.) 

Circulation. — Large  therapeutic  doses  tend  after  a  few  days  to 
produce  edema  of  the  skin  and  alimentary  tract,  as  shown  by 
pufhness  about  the  eyes  and  other  parts  of  the  body,  or  by  general 
edema,  nausea,  vomiting,  or  diarrhea.  This  is  due  to  increased 
transudation  of  serum,  from  heightened  permeability  of  the  sub- 
cutaneous and  submucous  capillaries,  and  of  those  of  the  alimen- 
tary tract.  In  some  cases  petechial  (capillary)  hemorrhages  are 
seen. 

The  effect  upon  the  blood-pressure  is  ordinarily  negative.  In 
severe  poisoning  the  blood- pressure  falls  from  loss  of  serum  by 
transudation,  the  heart  remaining  good. 

In  chronic  poisoning  there  may  be  fatty  degeneration  of  the 
heart  and  arteries. 

Blood. — It  is  upon  the  blood  or  blood-making  organs  that 
arsenic  seems  to  exert  its  most  valuable  therapeutic  effects.  The 
normal  bone-marrow  consists  essentially  of  erythroblastic  and 
leukoblastic  elements  and  fat  cells.  When  arsenic  is  administered 
for  long  periods  to  young  growing  animals,  the  bone-marrow  be- 
comes more  vascular,  with  increase  in  the  leukocytic  elements, 
decrease  in  the  fat,  and  little  if  any  change  in  the  erythrocytic 
elements  (Charteris,  1903).  There  is  no  change  in  either  the 
number  of  red  cells  or  the  percentage  of  hemoglobin  in  the  blood. 
Besredka,  from  sublethal  doses  in  rabibts,  noted  a  temporary 
diminution  of  the  leukocytes  in  the  blood,  followed  by  a  poly- 
morphonuclear leukocytosis. 

In  the  Manchester  epidemic,  in  which  over  3000  cases  of 
arsenic  poisoning  occurred  from  arsenic  in  beer,  the  cases  which 
came  to  postmortem  showed  these  changes.  But  some  of  the 
most  pronounced  cases  showed  extensive  degeneration  of  the 
marrow-cells  and  profound  anemia;  and  this  corresponded  with 
Charteris'  findings  that  "from  repeated  doses  large  enough  to 
cause  cachexia  and  emaciation  in  rabbits,  the  bone-marrow  under- 
goes hyaline  degeneration,  and  this  is  accompanied  by  decrease 
in  the  red  cells  and  hemoglobin." 

The  tendency  of  arsenic  is,  therefore,  to  increase  the  leuko- 
blastic elements  of  the  bone-marrow  and  the  leukocytes  in  the 
blood;  but  in  severe  chronic  poisoning,  to  induce  degeneration  of 
the  marrow-cells,  wasting,  and  profound  anemia. 

In  pernicious  anemia  there  is  an  increase  in  the  erythroblastic 
elements  of  bone-marrow,  associated  with  increased  destruction 
of  red  blood-corpuscles  (hemolysis) ;  in  leukemia,  there  is  an  in- 
crease in  the  leukoblastic  elements.    In  both  of  these  conditions 


ARSENIC    (ARSENUM)  507 

arsenic  is  employed,  at  times  with  benefit,  and  it  may  be  that  it 
acts  on  some  yet  undiscovered  toxin  or  parasite.  It  scarcely 
seems  to  be  curative,  however,  for  its  effects  do  not  last.  In 
chronic  malaria,  also,  there  is  a  destruction  of  red  cells  which  may 
be  more  or  less  checked  by  arsenic. 

Metabolism. — Long-continued  administration  lessens  the  ac- 
tivity of  the  liver,  so  that  it  forms  less  glycogen  and  has  less 
power  of  oxidation.  This  shows  in  the  urine  by  increased  amounts 
of  uric  acid  and  ammonia,  and  the  presence  of  leucin,  tyrosin,  and 
sarcolactic  acid,  the  total  nitrogen  of  the  urine  not  being  much 
changed.  There  may  be  a  swollen  liver  and  jaundice.  After 
a  fatal  dose  arsenic  is  usually  found  most  abundantly  in  the 
liver. 

Considerable  doses  not  only  cause  degenerative  changes  in 
the  bone- marrow,  but  have  a  strong  tendency  to  produce  fatty 
degeneration  in  the  liver,  kidneys,  heart,  arteries,  capillaries, 
the  epithelium  of  the  lungs  and  alimentary  tract,  and  striated 
muscle  and  skin  (dermis  and  epidermis). 

Bone. — In  growing  animals  of  poor  nutrition  it  tends  to  bring 
about  an  increase  in  the  density  of  bone,  the  cancellous  portion 
being  encroached  upon  by  the  increasing  thickness  of  the  hard 
bone.  This  may  be  due  to  the  increased  vascularity  of  the  bone- 
marrow.    In  adults  there  is  probably  no  effect  on  bone. 

Epithelium. — That  it  promotes  the  nutrition  of  the  skin  and 
epithelial  tissues  is  a  general  belief,  as  indicated  by  the  sale  of 
arsenic  complexion  tonics,  by  the  frequent  administration  of 
Fowler's  solution  to  horses  to  improve  their  appearance,  and 
by  the  use  of  arsenic  in  chronic  skin  diseases.  Thomas  Oliver 
gave  a  dog  with  short,  stubby  hair  one  grain  a  day,  and  the  hair 
became  sleek  and  long  (Allbutt's  System  of  Medicine) . 

Excretion. — It  is  excreted  in  the  urine  and  to  some  extent 
in  the  feces.  Traces  may  appear  in  the  gastric  juice,  the  bron- 
chial mucus,  the  sweat,  and  the  milk.  It  is  reported  as  appearing 
in  the  stomach  after  administration  by  rectum  (Kandikoff) 
or  hypodermatically.  Its  elimination  is  very  slow,  and  traces 
may  be  recovered  two  or  three  weeks  after  its  administration  has 
ceased. 

Tolerance. — Among  the  mountaineers  of  Styria,  Hungary, 
and  certain  parts  of  the  Punjab  there  are  a  number  of  persons 
known  as  "arsenic-eaters."  Knapp  and  Buchner  saw  a  man 
who  had  had  the  habit  for  thirty-six  years  take  2.6  grains  of 
orpiment  (arsenic  sulphide).  Knapp  administered  7  grains 
of  arsenic  trioxide  to  one  of  the  arsenic-eaters  of  Graz  without 
any  effect.  Maclagan  saw  a  man  take  6  grains.  It  is  taken 
about  once  or  twice  a  week,  and  is  said  to  act  somewhat  like 


508  PHARMACOLOGY    AND   THERAPEUTICS 

an  intoxicant,  increasing  combativeness,  stimulating  the  sex- 
ual appetite,  and  giving  a  feeling  of  strength  and  general  well- 
being. 

Besredka  injected  sublethal  doses  in  rabbits,  and  found  that 
the  leukocytes  usually  contained  arsenic,  but  not  in  the  cases 
that  proved  fatal.  He  thought  the  leukocytes  important  in 
preventing  the  poisoning.  Housmann  (1903)  found  that  in 
arsenic-habituated  dogs  the  mucous  membranes  of  the  alimentary 
tract  were  very  little  penetrable.  Later,  Cloetta  had  a  dog  which 
in  two  years  had  become  habituated  to  a  daily  dose  of  2.6  grams 
of  arsenic  trioxide  by  mouth.  He  found  that  all  of  this  but  0.13 
per  cent.,  i.  e.,  about  yo  grain  (0.003  gm.)  a  day,  passed  out 
with  the  feces.  On  administering  hypodermatically  one-six- 
tieth the  usual  daily  amount  the  dog  died  in  six  hours.  This 
showed  that  the  mucous  membrane  of  the  alimentary  tract  had 
become  resistant  to  absorption.  Cushny  states,  however,  that 
in  the  arsenic-eaters  a  large  amount  of  arsenic  is  found  in  the 
urine.  A  search  for  antibodies  in  these  eaters  has  proved  nega- 
tive. Christison  was  of  the  opinion  that  habit  tended  to  increase 
the  activity  of  the  inorganic  poisons  in  the  blood  rather  than  to 
diminish  it. 

Toxicology. — Acute  poisoning  is  generally  due  to  Paris-green 
(aceto-arsenite  of  copper),  or  white  arsenic,  taken  with  suicidal 
intent.  The  symptoms  come  on  slowly.  There  is  the  gradual 
onset,  in  fifteen  minutes  to  half  an  hour,  of  burning  in  the  esopha- 
gus, pain  in  the  abdomen,  nausea,  vomiting,  and  cramps,  fol- 
lowed by  violent  diarrhea  with  rice-water  or  bloody  stools,  ex- 
cessive thirst,  suppression  of  the  urine,  prostration,  and  low 
blood-pressure  from  great  transudation  of  serum.  The  rice- 
water  stools  are  composed  of  serum  containing  rolled-up  flakes 
of  mucus  and  epithelial  debris. 

In  fatal  cases  the  patient  either — (1)  Grows  rapidly  weaker 
and  dies  in  from  six  to  twenty-four  hours,  or  (2)  after  partial 
recovery  from  the  acute  symptoms  passes  slowly  into  a  condition 
of  collapse,  with  death  in  a  few  days.  In  the  latter  case  the  skin 
is  said  to  exhale  an  odor  of  garlic  (arseniureted  hydrogen).  At 
postmortem  there  is  fatty  degeneration  of  liver,  kidneys,  heart, 
etc.,  as  mentioned  above,  and  the  poison  is  found  in  nuclein 
combination,  chiefly  in  the  liver,  but  also  in  the  other  organs 
subject  to  degeneration,  viz.,  kidneys,  spleen,  lungs,  nervous 
system,  blood,  and  the  walls  of  the  stomach  and  intestines. 
Oliver  reports  that  his  dog  on  one  grain  of  arsenic  a  day  eventually 
died  from  chronic  poisoning,  but  that  no  arsenic  was  found  in  his 
liver  or  bones. 

After  acute  poisoning,  recovery  from  the  acute  symptoms  may 


ARSENIC    (ARSENUM)  509 

be  followed  by  the  manifestations  of  chronic  arsenic  poisoning. 
In  experimental  work  arsenic  is  given  to  produce  acute  vascular 
nephritis,  through  its  effect  upon  the  capillaries  of  the  glomeruli. 
Such  a  nephritis  may  occur  in  acute  or  subacute  poisoning  in 
man. 

The  treatment  is  thorough  lavage  of  the  stomach,  bearing  in 
mind  that  the  insoluble  arsenic  preparations  may  cling  closely 
to  the  inflamed  stomach-wall  and  corrode  it,  and  so  be  washed  off 
with  difficulty.  Freshly  prepared  ferric  hydroxide,  as  in  the 
U.  S.  P.  preparations,  "ferri  hydroxidum"  and  ''ferri  hydroxidum 
cum  magnesii  oxido,"  is  the  chemic  antidote.  It  oxidizes  the 
arsenous  to  an  arsenic  compound,  and  forms  the  iron  arsenate. 
(See  Iron.)  This  is  not  only  not  readily  absorbable,  but  when 
absorbed  is  less  readily  ionized,  and  is  therefore  less  poisonous. 
It  must  be  removed  by  lavage.  The  treatment  of  the  bowels 
presents  difficulties,  for  if  measures  are  taken  to  check  the 
diarrhea,  some  of  the  arsenic  may  be  retained  in  the  bowel  and 
absorbed.  Probably  a  large  dose  of  a  saline  cathartic,  followed, 
after  its  elimination,  by  large  doses  of  bismuth  subnitrate  and 
mucilaginous  drinks  or  olive  oil,  will  be  best  both  for  stomach  and 
bowels.  A  hot-water  bottle  or  atropine  may  relieve  the  abdomi- 
nal cramps.  Opium,  bismuth,  and  chalk  mixture  may  be  em- 
ployed, if  deemed  necessary,  for  the  diarrhea,  but  they  must  not 
be  used  too  early.  Large  doses  of  sodium  bicarbonate  are  said 
to  lessen  the  tendency  to  fatty  degeneration.  Further  treatment 
is  that  for  collapse,  bearing  in  mind  that  the  primary  collapse 
is  largely  due  to  loss  of  fluid  from  the  blood.  A  saline  infusion 
may  be  of  value,  but  transfusion  promises  better. 

Chronic  arsenic  poisoning  may  be  produced  from  the  gradual 
absorption  of  very  minute  quantities,  as  from  the  dyes  in  stock- 
ings and  the  coloring-matter  of  wall-paper,  carpets,  curtains, 
artificial  flowers,  etc.  Morse  reports  poisoning  in  an  infant  from 
the  blue  silk  lining  of  its  basket.  The  famous  epidemic  of  1 900, 
in  which  over  3000  cases  of  poisoning  were  discovered  in  England 
and  Wales,  occurred  from  minute  quantities  (T  to  f  of  a  grain 
of  arsenic  trioxide  per  gallon)  in  a  cheap  beer.  The  arsenic  was 
traced  back  to  the  sulphuric  acid  which  was  used  in  the  manu- 
facture of  the  glucose  employed  in  the  preparation  of  this  par- 
ticular brand  of  beer.  Starr  reports  that  of  42  samples  of  furs 
examined  in  New  York,  n  were  heavily  loaded  with  arsenic. 
Cases  of  poisoning  are  reported  from  the  therapeutic  use  of  the 
drug  in  chorea,  pernicious  anemia,  etc. 

The  onset  may  be  very  insidious,  and  the  stomach  and  bowel 
symptoms,  though  regularly  present,  may  not  be  of  such  startling 
character.     The  patients  look  chronically  ill,  and  have  loss  of 


5IO  PHARMACOLOGY   AND   THERAPEUTICS 

appetite,  nausea,  diarrhea  or  constipation,  abdominal  cramps, 
anemia,  irritability  of  temper,  insomnia,  debility,  and  emaciation. 
In  addition  there  may  be:  (i)  Swelling  of  the  liver  with  or  with- 
out jaundice,  associated  with  fatty  degeneration,  and  rarely  fol- 
lowed by  atrophy.  (2)  General  edema.  (3)  Various  skin 
eruptions.  (4)  A  dark  pigmentation  of  the  skin,  known  as  arsenic 
melanosis,  with  keratosis  of  palms  and  soles,  falling  of  the  hair 
and  nails,  and  other  trophic  manifestations.  (5)  Peripheral 
neuritis,  with  paralysis  or  ataxia,  pain,  etc.,  resembling  that  from 
alcohol. 

Death  has  occurred  from  one  grain  of  arsenic  trioxide  (Kun- 
kel)  and  from  half  an  ounce  of  Fowler's  solution  administered  in 
a  period  of  four  days  (Taylor). 

Cumulative  poisoning  from  medicinal  amounts  may  result 
from  the  slow  elimination.  The  first  indications  of  this  are 
usually  pumness  under  the  eyes,  nausea,  diarrhea,  abdominal 
cramps,  headache,  and  coryza.  From  the  arsenic  treatment  of 
chorea,  G.  M.  Swift  has  seen  the  following:  hemorrhage  from 
stomach,  hemorrhage  from  kidneys,  conjunctivitis,  neuritis, 
serious  anemia,  and  tedious  gastro-intestinal  inflammation  with 
albumin  in  the  urine.  Similar  reports  have  come  from  others 
from  the  use  of  arsenic  in  chorea,  pernicious  anemia,  etc.  Oliver 
reports  brown  pigmentation  in  children  treated  for  chorea. 

The  treatment  of  chronic  poisoning  is  stoppage  of  the  drug 
or  removal  of  the  patient  from  the  arsenic  bearing  substances, 
and  attention  to  the  general  health.  Potassium  iodide  is 
often  given,  but  Oliver  says  that  iodide  increases  the  pigmenta- 
tion of  the  skin,  and  does  not  promote  the  elimination  of 
the  drug. 

Therapeutics. — Locally. — Arsenic  trioxide  is  employed  in  the 
form  of  a  paste  as  a  caustic  for  lupus  and  superficial  epithe- 
liomata;  it  is  very  slow  in  action,  and  very  painful.  It  is  used  by 
dentists  to  destroy  the  nerves  of  teeth  by  setting  up  in  them  an 
inflammatory  reaction. 

Internally,  arsenic  preparations  are  used:  (1)  In  diseases 
of  the  blood  or  blood-making  organs,  as  chlorosis,  pernicious 
anemia,  leukemia,  Hodgkin's  disease,  chronic  malaria.  (2)  In 
certain  bone  and  joint  diseases  of  obscure  origin,  as  chronic 
rheumatism,  rheumatoid  arthritis,  osteitis  deformans,  osteo- 
malacia, and  rickets.  (3)  In  nervous  conditions,  as  chorea, 
hay-fever,  and  spasmodic  asthma.  Swift  says  it  does  more  harm 
than  good  in  chorea.  (4)  In  chronic  non-parasitic  skin  diseases 
(not  in  acute  inflammatory  skin  diseases).  (5)  In  any  run-down 
conditions  with  anemia  and  poor  nutrition.  Von  Noorden  and 
others   have   found   arsenic   preparations   useless   in   diabetes, 


ARSENIC    (ARSENUM)  511 

though  Salkowski  reported  that  in  animals  poisoned  by  arsenic 
no  artificial  diabetes  could  be  produced  by  puncture  of  the 
fourth  ventricle  or  by  curare. 

The  organic  preparations  have  been  employed  in  trypano- 
somiasis, Vincent's  angina,  relapsing  fever,  syphilis,  leprosy, 
pellagra,  malaria,  splenic  anemia,  leukemia,  etc.,  with  varying 
results.  It  is  claimed  that  arseno-phenyl-glycin  is  the  best  in 
trypanosomiasis  (Wendelstadt,  Roehl).  Atoxyl  has  a  very 
strong  tendency  to  produce  optic  nerve  atrophy  and  permanent 
blindness. 

Administration. — Arsenic  trioxide  is  generally  used  with  iron 
or  strychnine  in  pills  or  as  an  elixir.  Fowler's  solution  is  mostly 
employed  by  itself  in  drop  doses,  one  drop  from  a  bottle  lip  or 
standard  dropper  being  practically  one  minim.  It  has  become 
customary  to  begin  with  a  small  dose,  say  three  drops  three  times 
a  day,  and  to  increase  the  dose  each  day  by  a  drop  or  two  until 
the  patient  shows  the  first  signs  of  cumulative  poisoning.  It 
would  seem  as  if  the  harmful  metabolic  effects  of  the  drug  should 
prohibit  such  a  method  of  administration;  and  there  are  numer- 
ous instances  of  neuritis,  pigmentation  of  the  skin,  and  other 
undesirable  manifestations  which  bear  witness  to  the  inad- 
visability  of  giving  this  drug  to  its  physiologic  limit. 

Salvarsan. — This  remedy  and  neo-salvarsan,  its  close  relative^ 
are  far  and  away  beyond  the  others  in  syphilis.  In  a  number  of 
cases  a  single  dose  of  salvarsan  apparently  kills  all  the  syphilitic- 
spirochetes.  But  though  salvarsan  is  a  very  important  addition 
to  our  materia  medica,  it  has  not  come  fully  up  to  our  early  hopes. 
In  most  cases  it  does  not  kill  all  and  must  be  repeated  one  or 
several  times,  the  mercury  treatment  being  instituted  in  addition. 
A  number  of  syphilologists  are  using  repeated  doses  at  week 
intervals.  The  salvarsan  is  regularly  followed  by  an  exceedingly 
prompt  subsidence  of  any  acute  manifestations  of  the  disease, 
the  response  being  most  noticeable  in  the  primary  stage  and 
least  in  the  tertiary.  Fox  thinks  that  in  the  later  stages  it 
fails  to  show  any  advantage  over  mercury,  as  judged  by  the 
serum  tests. 

General  paresis,  locomotor  ataxia,  and  others  of  the  para- 
syphilitic  diseases  have  failed  in  most  instances  to  give  any  re- 
sponse whatever.  But  in  such  lesions  of  the  central  nervous 
system,  Swift  and  Ellis  are  using  the  following  method  at  the 
Rockefeller  Institute.  They  give  the  patient  an  intravenous  of 
salvarsan,  then  an  hour  later  draw  off  several  cubic  centimeters 
of  blood,  the  serum  from  which  is  mixed  with  salt  solution  and 
injected  into  the  cerebrospinal  canal.  The  process  may  be  re- 
peated a  number  of  times.     In  cases  of  locomotor  ataxia  they 


512  PHARMACOLOGY   AND   THERAPEUTICS 

have  obtained  an  improvement  in  the  cell  count  and  in  the 
globulin  content  of  the  spinal  fluid,  with  some  clinical  improve- 
ment. 

Salvarsan  has  been  employed  in  leukemia,  splenic  anemia, 
Banti's  disease,  pernicious  anemia,  kala-azar,  malaria,  leprosy, 
pellagra,  relapsing  fever,  tuberculosis,  filaria,  frambesia,  and 
many  other  conditions,  with  some  reported  good  effects  and  many 
failures. 

It  has  become  the  regular  custom  to  administer  salvarsan 
intravenously,  because  in  a  number  of  instances  its  intramuscular 
injection  was  followed  by  necrosis  and  the  formation  of  an  ab- 
scess, the  arsenic  remaining  unabsorbed.  A  number  of  deaths 
have  occurred  from  its  use. 

The  untoward  effects  are : 

i.  The  Jarisch-Herxheimer  reaction,  in  which  the  secondary 
eruption  becomes  darker  and  appears  to  spread  for  a  number  of 
hours.  It  is  believed  to  be  the  result  of  insufficient  dosage  at 
the  outset. 

2.  Irritation  of  the  tissues,  with  lymphangitis,  from  leakage 
in  the  neighborhood  of  the  vein. 

After-effects. — The  usual  ones  are  headache,  nausea,  malaise, 
lasting  from  twelve  to  twenty-four  hours. 

Contraindications. — i.  Severe  non-syphilitic  retinal  and  op- 
tic diseases.  2.  Severe  heart  and  vascular  disease.  3.  Severe 
lung  affections.  4.  Severe  non-syphilitic  kidney  affections. 
5.  Advanced  degenerative  processes  in  the  central  nervous 
system. 

In  infants  the  drug  must  be  used  with  caution,  as  the  destruc- 
tion of  the  germ  liberates  an  undue  amount  of  the  endotoxins. 


ANTIMONY 

The  only  official  salt  is  the  double  tartrate  of  antimony 
and  potassium,  or  tartar  emetic,  2K(SbO).C4H406.  It  is  soluble 
in  16  parts  of  water. 

Preparations  and  Doses. — Antimony  and  potassium  tartrate, 
Yq  grain  (0.006  gm.). 

Wine  of  antimony,  0.4  per  cent.,  15  minims  (1  c.c).  The  wine 
enters  into  compound  licorice  mixture  (mistura  glycyrrhizae 
composita),  making  about  TV  grain  of  tartar  emetic  in  each 
teaspoonful. 

Compound  syrup  of  squill,  or  Coxe's  hive  syrup,  0.2  per  cent, 
with  senega  and  squill.    Dose,  30  minims  (2  c.c). 

Pharmacologic  Action. — Locally  it  is  irritant  and  was  formerly 
used  as  a  pustulant. 


PHOSPHORUS  513 

Systemically,  it  resembles  arsenic,  but  it  is  absorbed  with 
greater  difficulty  and  has  a  nauseant  effect,  as  a  consequence 
of  which  it  tends  to  fluidify  and  promote  the  flow  of  mucus  in 
the  respiratory  tract.  It  was  formerly  employed  in  dose  of 
yi  to  2  grains  (0.03-0.12  gm.)  as  an  emetic;  but  its  chief  use 
now  is  in  colds  in  which  the  respiratory  mucus  is  thick  and 
tenacious. 

It  has  recently  been  extensively  employed  in  trypanosomia- 
sis, its  action  being  similar  to  that  of  the  organic  arsenic 
preparations.  Hypodermatically,  it  is  very  painful,  but  it  may 
be  given  intravenously  in  saline,  \  grain  (0.01  gm.)  every 
four  days;  or  in  the  form  of  antimony  lithium  tartrate  by 
mouth  in  dose  of  iJE^  to  2  grains  (0.1-0.13  gm.)  in  3  pints 
(1500  c.c.)  of  water  daily  (Camac). 

Acute  poisoning  has  been  observed  in  typesetters,  and  is 
usually  mistaken  for  plumbism.  The  symptoms  are:  anemia, 
poor  nutrition,  constipation,  ready  fatigue,  nervousness,  in- 
somnia, dizziness,  headache,  and  pain  in  the  muscles  or  nerves. 
The  blood-pressure  tends  to  be  low,  and  the  blood  to  show  dimin- 
ished leukocytes  and  eosinophilia.  The  antimony  may  be 
found  in  the  stools.  The  treatment  is  the  same  as  that  for 
chronic  lead-poisoning. 


PHOSPHORUS 

Phosphorus  is  insoluble  in  water,  but  soluble  in  ether,  chloro- 
form, and  the  oils.  It  is  readily  oxidized  to  phosphorous  acid, 
which  is  an  inert  compound.  It  resembles  arsenic  in  its  action, 
but  is  less  irritant  locally,  and  has  a  greater  tendency  to  produce 
fatty  degenerations.  Charteris  (1903),  in  his  studies  on  the 
bone-marrow,  administered  it  subcutaneously  to  rabbits.  In 
the  early  stages  the  marrow  showed  hyperemia  and  increase  in 
the  leukoblastic  tissue ;  after  prolonged  administration  the  marrow 
was  markedly  degenerated.  In  growing  animals  the  growth  of 
bone  has  been  decidedly  promoted,  the  cancellous  portion  giving 
way  to  the  development  of  hard  bone.  In  adult  animals 
Charteris  found  no  change  in  the  bones. 

Toxicology. — Acute  poisoning  somewhat  resembles  that  from 
arsenic.  After  a  latent  period,  which  may  be  several  hours, 
there  are  burning  in  the  stomach,  abdominal  pain,  and  vomiting. 
At  first  the  liver  is  swollen,  but  it  soon  undergoes  a  rapid  atrophy 
of  the  type  of  acute  yellow  atrophy.  Jaundice  usually  comes  on 
in  twenty-four  hours.  There  are  leucin,  tyrosin,  and  other 
incompletely  oxidized  bodies  in  the  urine.  The  local  antidote 
is  an  oxidizing  agent,  such  as  peroxide  of  hydrogen  or  potassium 

33 


514  PHARMACOLOGY  AND  THERAPEUTICS 

permanganate.  Oils  should  not  be  employed  unless  promptly- 
washed  from  the  stomach. 

Chronic  poisoning  is  to  be  seen  among  the  makers  of  matches. 
Its  chief  manifestation  is  "fossy  jaw,"  a  condition  of  necrosis 
of  the  jaw  bones  which  is  incurable,  and  often  necessitates 
extensive  curetage  of  the  parts  to  check  the  horrible  cadaverous 
odor.  It  may  even  require  removal  of  the  entire  maxilla.  Char- 
teris  laid  bare  the  periosteum  of  the  lower  jaw  of  rabbits,  and 
repeatedly  exposed  them  to  phosphorus  fumes,  but  could  not 
get  necrosis. 

Therapeutics. — Phosphorus  has  been  used  in  dose  of  y^o- 
grain  (0.0006  gm.)  in  the  treatment  of  rickets  and  osteomalacia. 
It  is  given  in  the  form  of  a  pill,  an  elixir,  or  a  1  per  cent,  solution 
in  olive  oil.    It  is  probably  mostly  inert. 

The  hypo  phosphites  (Na2P02,  CaP02,  etc.)  have  been  much 
employed  as  nerve  tonics.  The  belief  that  they  furnish  phos- 
phorus to  the  nerve  tissues  is  negatived  by  the  fact  that  they  pass 
unchanged  through  the  system,  and  can  be  almost  entirely 
recovered  from  the  urine  as  hypophosphites.  The  compound 
syrup  of  the  hypophosphites  is  official,  dose,  2  drams,  which  con- 
tains TV  grain  of  strychnine,  -g-  grain  of  quinine,  and  iron  and 
manganese.  The  strychnine  and  iron  are  the  essential  con- 
stituents. 

The  Glycerophosphates. — Calcium  glycerophosphate,  CaP04. 
C3H5(OH)2  is  soluble  in  20  parts  of  cold  water;  the  sodium  salt, 
Na2P04.C3H5(OH)2,  is  very  soluble  in  water  and  is  deliquescent. 
It  is  to  be  obtained  only  in  50  per  cent,  solution.  They  are 
esters  of  phosphoric  acid,  and  their  administration  results  in  an 
increase  in  the  urinary  phosphates.  They  are  at  the  present 
time  much  in  use  as  general  " nerve  tonics,"  and  have  largely 
replaced  the  useless  hypophosphites.  But  there  is  no  satisfac- 
tory evidence  that  they  increase  the  phosphorus  in  the  nervous 
tissues,  and  there  is  abundant  evidence  that  the  body  can  get 
its  needed  phosphorus  quite  as  well  from  the  inorganic  phos- 
phates; at  least  this  is  the  case  in  hens  and  ducks,  which  give 
out  a  large  amount  of  phosphorus  in  their  eggs  in  the  form  of 
lecithin.  Fingerling  tried  to  enrich  the  milk  of  goats  by  the 
administration  of  phosphorus  compounds.  He  found  that, 
even  when  the  food  was  deficient  in  phosphorus,  the  organic 
phosphorus  compounds  exerted  no  more  favorable  influence 
than  the  inorganic  ones. 

There  are  no  pharmacopeial  preparations,  but  the  National 
Formulary  gives  an  elixir  containing  1  grain  (0.06  gm.)  of  sodium 
glycerophosphate  and  ]4  grain  (0.03  gm.)  of  calcium  glycero- 
phosphate in  each  dram  (4  c.c). 


THE   IODIDES 


515 


Lecithin  is  a  glycerophosphoric  acid,  substituted  by  two 
fatty  acid  radicals,  and  combined  with  choline.  It  contains 
about  4  per  cent,  of  phosphorus,  and  probably  sets  free  phos- 
phoric acid.  It  occurs  in  most  animal  and  plant  cells,  but  es- 
pecially in  the  brain  and  nerves,  yolk  of  egg,  fish-eggs,  milk 
(especially  woman's  milk),  blood-plasma,  and  bile.  An  ordinary 
mixed  diet  may  furnish  as  much  as  1  to  2  drams  (4-8  gm.)  per 
day  (Von  Noorden).  It  is  broken  up  by  the  pancreatic  juice 
into  glycerophosphoric  acid,  fatty  acids  and  choline  (Dixon). 
When  used  in  the  emulsification  of  fats  it  promotes  their  ab- 
sorption. 

It  is  "a  very  important  material  for  building  up  the  compli- 
cated phosphorized  nuclein  substances  of  the  cell  and  cell 
nucleus"  (Hammarsten) .  Its  administration  in  laYge  amounts 
in  anemia  tends  to  increase  the  hemoglobin  and  red  cells  and  to 
improve  the  nutrition.  Nerking,  by  the  injection  of  a  lecithin- 
saline  solution  in  rabbits,  was  able  to  cut  short  or  abolish  anes- 
thesia and  narcosis.  He  considered  this  evidence  in  favor  of 
the  Meyer-Overton  theory  of  narcosis. 

When  eggs  and  milk  are  available,  it  hardly  seems  of  advan- 
tage to  prescribe  the  commercial  lecithin  in  doses  of  5  or  10 
grains  (0.3-0.7  gm.). 


THE   IODIDES 

Preparations  and  Doses. — Iodine  (iodum),  -^  grain  (0.006 
gm.). 

Sodium  iodide,  potassium  iodide,  10  grains  (0.7  gm.);  diluted 
hydriodic  acid,  10  per  cent.,  1  dram  (4  c.c). 

Tincture  of  iodine,  7  per  cent,  iodine  and  5  per  cent,  potas- 
sium iodide,  with  alcohol. 

Compound  solution  of  iodine  (Lugol's  solution),  an  aqueous 
solution  of  5  per  cent,  of  iodine  and  10  per  cent,  of  potassium 
iodide. 

Iodoform,  CHI3,  4  grains  (0.25  gm.). 

Iodipin  is  oil  of  sesame  in  which  the  unsaturated  acids  have 
been  treated  with  iodine,  and  contains  25  per  cent,  of  iodine. 
Dose,  1  dram  (4  c.c.)  in  emulsion.  According  to  Leathes  (191 1), 
iodipin  can  be  absorbed  and  stored  up  as  fat  without  giving 
up  its  iodine  to  the  tissues. 

Sajodin  is  mono-iodo-behenate  of  calcium,  a  nearly  tasteless 
white  powder,  dose,  15  grains  (1  gm.). 

Pharmacologic  Action. — Externally. — For  the  external  action 
of  iodine  see  Counterirritants  and  Disinfectants. 

Internally. — The  alkaline  iodides  are  freely  soluble  in  water 


516  PHARMACOLOGY  AND  THERAPEUTICS 

and  have  a  disagreeable  bitter  taste  and  a  salt  action.  Locally 
they  are  irritant,  so  require  proper  dilution  before  their  admin, 
istration.  They  have  always  been  considered  valuable  remedies, 
but  their  mode  of  action  has  been  the  subject  of  much  surmise. 
It  is  generally  understood  that  they  promote  the  flow  of  saliva 
and  respiratory  mucus,  that  they  increase  the  activity  of  the 
thyroid  gland,  and  that  they  tend  to  lessen  the  viscosity  of  the 
blood.  Mueller  and  Inada  hold  that  the  viscosity  is  lessened, 
but  Determann  says  not. 

Absorption  and  excretion  are  rapid,  iodine  being  recoverable 
from  the  saliva  and  urine  a  few  minutes  after  their  ingestion. 
Hanzlik  (191 2)  found  that  with  sodium  iodide  in  1  to  10  per 
cent,  solution  there  was  a  rapid  initial  absorption  of  50  to  75 
per  cent,  of  the  total,  and  then  a  marked  inhibition  of  absorp- 
tion due  to  a  local  effect  on  the  absorbing  epithelium.  He  found 
also  that  the  application  to  the  mucous  membrane  of  0.2 
to  1  per  cent,  sodium  chloride  prevented  absorption  of  the 
iodide. 

Unlike  many  salts,  they  do  not  remain  in  the  body,  but  are 
excreted  rapidly  by  the  kidneys.  Seventy-five  per  cent,  of 
the  dose  appears  in  the  urine  inside  of  twenty-four  hours.  The 
remainder  may  remain  in  organic  combination  in  the  body. 
Rowntree,  Fitz,  and  Geraghty  found  the  excretion  retarded  in 
experimental  chronic  passive  congestion  of  the  kidney.  Swift 
(Rockefeller  Institute)  reported  that  iodine  is  not  found  in  the 
cerebrospinal  fluid,  even  after  very  large  doses  by  mouth. 

Because  of  its  excretion  in  the  saliva,  it  may  produce  a  very 
unpleasant  metallic  taste  in  the  mouth,  with  coated  tongue. 
To  avoid  this,  it  is  recommended  to  gargle  with  a  solution  of 
sodium  bicarbonate  during  the  iodide  administration. 

Action  on  the  Thyroid  Gland. — (See  next  article  on  Thyroid 
Glands.) 

Marine  and  Lenhart  (1909)  found  that  iodine  given  in  any 
form  was  taken  up  by  the  thyroids,  whether  these  were  normal, 
colloid,  or  hyperplastic;  that  the  subjects  with  hyperplastic 
glands  lost  weight  for  one  or  two  weeks,  then  rapidly  gained; 
and  that  iodine  hastened  the  tendency  of  all  active  hyperplasias 
to  revert  to  colloid. 

Many  of  the  experiments  have  suggested  that  much  of  the 
benefit  of  iodides  in  a  number  of  conditions  may  be  due  to  in- 
creased thyroid  activity. 

Circulation. — In  normal  persons  or  laboratory  animals  iodides 
have  no  measurable  effect  upon  the  blood-pressure,  but  in  those 
with  high  arterial  tension  they  have  a  tendency  to  lower  it. 
This  effect  is  probably  due  both  to  the  lessening  of  the  viscosity 


THE    IODIDES  517 

of  the  blood  and  to  the  increase  in  thyroid  activity.  Their  value 
in  arteriosclerosis  may  possibly  be  due  to  improved  blood-flow 
in  the  vasa  vasorum,  owing  to  diminished  viscosity  of  the  blood. 
Mueller  and  Inada  (1904)  found  a  decrease  in  the  viscosity, 
Determann  not.  Adam  (1909)  thought  that  ordinary  doses 
were  too  small  to  cause  decreased  viscosity,  though  large  amounts 
would  do  so. 

Respiratory  Organs. — There  is  increased  fluidity  of  mucus 
in  the  nose,  throat,  and  bronchi.  This  is  considered  by  Hender- 
son and  Taylor  (1910)  to  be  a  reflex  effect.  In  tuberculosis, 
iodides  are  believed  to  be  harmful,  because  of  their  tendency 
to  interfere  with  connective-tissue  formation  and  to  soften  the 
tubercles;  for  this  promotes  the  spread  of  the  disease.  In  cases 
with  doubtful  physical  signs  of  tuberculosis,  it  is  a  common 
custom  to  administer  iodides  to  "bring  out  the  rales."  But  the 
author's  clinical  experience  coincides  with  that  of  others  in 
finding  this  a  dangerous  practice,  and  the  experiments  of 
Sorel  (1909)  give  additional  proof  that  tuberculosis  is  a  contra- 
indication to  iodide.  Sorel  infected  guinea-pigs  with  the  tubercle 
bacillus,  then  administered  potassium  iodide  to  a  certain  num- 
ber of  them.  The  iodide  pigs  died  of  tuberculosis  some  weeks 
earlier  on  the  average  than  those  which  did  not  get  the  iodide. 
It  has  been  reported  also  that  weak  doses  of  iodide  in  the  tuber- 
culous will  give  a  reaction  similar  to  that  of  fair  doses  of  tuber- 
culin, a  reaction  which  may  help  to  establish  a  diagnosis,  but  is 
not  without  danger.  Iodide  is  said  also  to  give  such  a  reaction 
in  lepers. 

In  asthma  associated  with  chronic  bronchitis  and  emphysema 
the  action  of  iodides  is  probably  an  expectorant  one. 

Untoward  Actions. — Besides  the  local  irritation  of  the  stomach, 
the  most  frequent  undesirable  effects  are  those  upon  the  skin 
and  mucous  membranes. 

1.  Skin. — The  skin  lesion  usually  shows  as  irregularly  scat- 
tered pimples,  the  chief  sites  of  which  are  the  face,  shoulders, 
neck,  and  back.  It  has  been  thought  that  the  skin  affection 
was  due  to  elimination  of  the  drug  by  the  sebaceous  glands,  and 
its  decomposition  by  the  fatty  acids  of  the  sebaceous  secretion. 
But  many  investigators  have  failed  to  find  either  free  iodine 
or  iodide  in  the  sebaceous  secretion,  and  the  dermatopathologists 
agree  that  the  changes  begin  in  the  papillary  layer  and  not  in 
the  glands  (Stelwagon). 

Other  skin  lesions  than  acne  may  make  their  appearance, 
as  urticaria  or  a  vesicular  or  bullous  or  hemorrhagic-bullous  or 
purpuric  eruption.  A  few  cases  of  carbuncle  formation  with 
serious  destruction  of  the  subdermal  tissues  are  reported,  even 


518  PHARMACOLOGY  AND   THERAPEUTICS 

resulting  in  death.  The  serious  eruptions  usually  occur  in 
patients  with  much  lowered  vitality,  and  especially  in  those  with 
chronic  nephritis. 

2.  Mucous  Membranes. — The  mucous  membranes  chiefly 
irritated  are  the  conjunctivae  and  those  of  nose,  throat,  bronchi, 
and  stomach.  A  not  unusual  effect  is  that  of  a  severe  cold  in 
the  head,  with  watery,  injected  eyes,  headache,  and  general 
malaise;  there  may  be,  in  addition,  nausea,  salivation,  and  tender 
teeth  and  gums.  The  patients  think  they  have  influenza.  A 
number  of  cases  of  edema  of  the  glottis  have  been  reported,  also 
purpuric  eruptions  on  the  mucous  membranes,  and  inflammation 
and  swelling  of  the  parotid  glands. 

It  has  been  ascertained  by  extensive  clinical  experience  that 
the  minor  eruptions  are  more  frequent  from  the  smaller  doses 
of  5  or  10  grains,  and  that  they  sometimes  disappear  when  the 
dose  is  increased. 

Prophylactic  measures  against  the  lesions  of  skin  and  mucous 
membranes  are  great  cleanliness  of  skin  and  mouth,  alkalies, 
and  arsenic.  Some  think  that  the  sodium  iodide  is  less  irritating 
than  the  other  salts. 

Iodide  Fever. — In  a  case  of  plumbism,  Oliver  reports  a  tem- 
perature of  101.80  F.,  and  albumin  in  the  urine  from  5-grain 
doses  of  potassium  iodide.  In  a  case  of  chronic  rheumatism 
of  the  author's  (191 2)  10  grains  of  potassium  iodide  three  times 
a  day  caused  swelling  and  intense  burning  of  the  face  and  hands, 
fever,  and  eventually  delirium.  It  was  learned  that  the  same 
phenomena  had  followed  iodide  the  previous  year.  Konried 
reports  two  cases  of  iodide  fever,  one  of  them  being  from  the 
local  use  of  an  ointment. 

Chronic  iodism  is  a  state  in  which  there  are  anemia  and  emacia- 
tion, nervousness,  tachycardia,  and  loss  of  sexual  power.  Much 
iodide,  even  without  any  poisonous  symptoms,  tends  to  lower 
the  body  tone  and  to  depress  the  spirits. 

Therapeutics. — Iodides  are  believed  to  be  more  or  less  specific 
in  tertiary  syphilis  and  actinomycosis.  According  to  Jonathan 
Hutchinson,  "Over  the  tertiary  manifestations  of  syphilis,  the 
gumma,  whether  of  skin,  cellular  tissue,  coats  of  arteries,  cere- 
bral meninges,  or  periosteum,  potassium  iodide  exercises  almost 
as  definite  an  influence  as  mercury  over  the  earlier  ones. " 

Iodides  are  also  employed  in: 

1.  The  asthma  of  emphysema  and  chronic  bronchitis. 

2.  Arteriosclerosis  and  some  other  conditions  with  chronic 
connective-tissue  production;  not  in  cirrhosis  of  the  liver  or 
chronic  nephritis  (unless  for  arterial  hypertension). 

3.  Aneurysm  of  the  aorta. 


Fig>  s8  _ Dermatitis  medicamentosa  of  pustulobullous  type,  following  inges- 
tion of  potassium  iodide.  Principally  upon  the  face,  with  some  pustular  lesions  on 
the  neck  and  shoulders.     Subsided  upon  withdrawal  of  the  drug,  and  recurred  on 


experimental  readministration  (Stelwagon). 


Fig  59  —Dermatitis  medicamentosa  of  a  bullous  type,  from  the  ingestion  of 
potassium  iodide  in  a  woman  aged  fifty.  Face,  neck,  forearms,  and  hands  in- 
volved and  the  seat  of  considerable  edematous  swelling  and  variously  sized  blebs. 
In  some  parts  blebs  became  confluent,  broke,  and  uncovered  a  superficially  ex- 
coriated surface,  as  shown  in  cut.  Recovery  without  any  scarring  or  other  trace. 
Patient  had  a  weak  heart  (Stelwagon). 


THYROID    GLAXD  519 

4.  Cases  with  high  arterial  tension,  from  whatever  cause. 

5.  Chronic  rheumatism  or  rheumatoid  affections. 

6.  Poisoning  by  the  heavy  metals.  Oliver  believes  them 
of  little  or  no  use  in  promoting  the  excretion  of  metallic 
poisons. 

7.  Colloid  goiter — Schondorff  calls  attention  to  the  good 
results  that  have  been  obtained  from  iodides  and  from  sea 
plants  containing  iodine. 

It  is  generally  thought  that  they  should  not  be  used  in  hyper- 
thyroidism. Krehl  advises  strongly  against  their  use,  as  he  has 
seen  latent  hyperthyroidism  change  under  small  doses  of  iodide 
into  a  permanently  intractable  active  form.  But  Marine  and 
Lenhart  (1909)  point  out  that  in  the  hyperplastic  glands  small 
doses  tend  to  hasten  the  change  to  colloid,  which  may  be  desir- 
able.   They  advise  very  small  doses. 

Contraindications. — The  chief  of  these  is  pulmonary  tuber- 
culosis. 

Administration. — Potassium  or  sodium  iodide  may  be  given 
in  milk  ("best  way  of  all" — Dock)  or  in  saturated  aqueous 
solution,  or  in  dilute  solution  flavored  with  compound  syrup 
of  sarsaparilla  or  syrup  of  orange-peel.  Of  the  saturated  solu- 
tion of  potassium  iodide  in  water,  1  minim  is  practically  a  drop, 
as  dropped  from  a  bottle  mouth  or  standard  dropper,  and  it 
contains  1  grain.  In  syphilis  this  is  often  begun  by  three  doses 
a  day  of  10  to  15  drops  (0.7-1  c.c),  this  dose  being  increased  one 
drop  each  day  until  45  or  60  grains  (3  to  4  gm.)  of  the  drug  are 
being  taken  three  times  a  day.  For  convenience,  compressed 
tablets  may  be  employed,  but  they  should  be  dissolved  before 
swallowing. 

THYROID   GLAND 

Desiccated  thyroid  glands  (glandulae  thyroideae  siccae)  are 
the  dried  thyroids  of  various  domestic  animals.  They  are 
administered  in  tablet  or  capsule  form,  dose,  2  to  5  grains  (0.12- 
0.3  gm.)  one  to  three  times  a  day.  The  commercial  article 
regularly  contains  iodine,  and  yields  by  special  treatment  various 
principles,  such  as  thyroiodin  and  thyreoglobulin. 

Iodine  Content. — Most  thyroid  glands  contain  iodine.  In 
the  dried  glands  of  adult  human  beings  Vincent  found  0.3  to 
0.9  per  cent.;  in  the  dried  glands  of  seven  dogs  Seidell  obtained 
0.036  to  0.271  per  cent.;  and  in  ten  sheep's  thyroids  dried,  Simp- 
son and  Hunter  obtained  0.048  to  0.383  per  cent.  But  in  the 
thyroids  of  many  children  and  those  of  certain  individuals  of 
various  species,  as  the  ox,  horse,  pig,  sheep,  etc.,  iodine  has  been 


520  PHARMACOLOGY   AND   THERAPEUTICS 

present  in  mere  traces  or  totally  absent.  Yet  these  animals 
seem  to  get  along  as  well  as  those  with  iodine-containing  thyroids, 
and  cannot  be  distinguished  from  them ;  and  after  thyroidectomy 
they  show  just  as  severe  symptoms  as  those  with  even  a  high 
percentage  of  iodine  in  their  thyroids.  It  is  evident,  therefore, 
as  Vincent  says,  that  thyroid  gland  free  from  iodine  seems  to 
meet  the  needs  of  the  body  apparently  as  well  as  that  containing 
iodine. 

But  the  experiments  of  Baumann,  Roos,  Hunt,  and  many 
others  point  out  the  ability  of  the  gland  to  take  iodine  given  by 
mouth  into  organic  combination,  and  Hunt  and  Seidell  have 
shown  that  there  is  a  parallelism  between  the  iodine  content  of 
thyroid  and  its  physiologic  activity.  In  their  experiments,  46 
dogs  were  used.  On  two  successive  days,  1.5  to  2  gm.  of  potas- 
sium iodide,  or  1  to  1.3  gm.  of  iodoform  (CHI3) ,  were  adminis- 
tered by  mouth,  and  on  the  third  day  the  dog  was  killed.  The 
thyroids  of  the  iodoform  dogs  averaged  0.3  per  cent,  of  iodine, 
and  of  the  iodide  dogs,  0.148  per  cent. ;  while  those  of  the  controls 
ranged  between  0.106  and  0.129  per  cent.  These  thyroids  were 
then  tested  on  rats  and  mice,  and  were  found  to  decrease  the 
resistance  of  rats  and  mice  to  poisoning  by  morphine  and  of 
rats  to  poisoning  by  acetonitril,  practically  in  proportion  to  the 
percentage  of  iodine  present. 

Pharmacology. — Protein  Metabolism. — Roos  (1899)  found  that 
thyroid  rich  in  iodine  caused  a  marked  increase  in  nitrogen 
excretion;  that  thyroid  poor  in  iodine  caused  scarcely  any  in- 
crease, and  that  iodine-free  thyroid  had  no  effect  at  all  on  the 
nitrogen.  Oswald  found  the  same  to  be  true  of  thyreoglobulin, 
the  presence  or  absence  of  iodine  determining  the  increase  or 
otherwise  of  nitrogen  metabolism.  Schondorff,  after  a  series 
of  experiments  of  long  duration,  came  to  the  same  conclu- 
sion. It  may  therefore  be  taken  as  established  that  commercial 
thyroid,  which  regularly  contains  iodine,  increases  protein 
loss. 

Fat  Metabolism. — As  long  ago  as  1894  thyroid  was  recom- 
mended in  obesity.  Stuve,  in  tests  with  healthy  men,  found  the 
consumption  of  oxygen  increased  about  20  per  cent.,  and  Thiele 
and  Nehring  obtained  similar  results.  In  myxedema  Magnus- 
Levy  recorded  an  increase  of  80  per  cent.  These  figures  indicate 
a  loss  of  fat  out  of  proportion  to  the  loss  of  protein.  Marine 
and  Williams  (1908)  found  in  a  dog  that  in  eighteen  days  11  gm. 
of  dried  sheep's  thyroid  containing  0.0292  per  cent,  of  iodine 
caused  no  loss  of  weight;  while  in  another  dog,  in  the  same  time, 
n  gm.  of  a  preparation  containing  0.1092  per  cent,  of  iodine 
caused  a  loss  in  weight  of  454  gm.     There  are  many  clinical 


THYROID    GLAND  521 

reports  pointing  to  the  value  of  thyroid  in  obesity,  but  it  must 
be  remembered  that,  with  the  reduction  of  fat,  there  is  also 
excessive  protein  destruction,  and  this  is  a  serious  feature  in 
any  reduction  cure. 

In  the  many  experiments  with  thyroid  the  numeric  indicator 
of  the  activity  of  the  preparation  would  seem  to  be  the  per- 
centage of  iodine.  And  this  has  led  to  the  belief,  on  the  part  of 
some  investigators,  that  commercial  thyroid  is  merely  a  special 
form  in  which  iodine  may  be  administered  in  organic  combina- 
tion. That  this  is  true  in  some  cases  is  indicated  by  the  resem- 
blance of  the  effects  to  those  of  other  iodine  preparations;  but 
in  thyroid  absence,  as  in  myxedema  or  cretinism  or  after  thy- 
roidectomy, no  other  iodine  preparation  is  of  any  avail.  The 
fact,  however,  that  thyroid  activity  increases  with  its  iodine 
content  has  led  to  the  adoption  of  a  standard  for  commercial 
preparations  of  not  less  than  0.2  per  cent,  of  iodine. 

Bone. — Many  surgeons  have  attested  to  the  power  of  thy- 
roid to  promote  union  in  delayed  fractures,  and  Bircher 
(1910)  has  found  that  it  promotes  the  growth  of  bone  in  normal 
animals. 

Toxicology. — An  intravenous  dose  causes  a  slowing  of  the 
pulse  and  a  fall  in  blood-pressure.  As  this  is  prevented  by 
atropine  or  by  cutting  the  vagi,  it  must  be  due  to  stimulation 
of  the  vagus  center. 

When  the  drug  is  given  in  full  dosage  for  long  periods  to 
dogs,  cats,  horses,  sheep,  etc.,  and  especially  when  given  to 
monkeys  and  man,  it  produces  a  regular  group  of  effects.  There 
are  anemia,  emaciation,  and  muscular  weakness,  excessive  sweat- 
ing, a  tendency  to  fever,  headache,  nervousness,  tremor  of  face 
and  limbs,  various  pains  and  tingling  or  pricking  sensations  or 
paralyses,  increased  heart-rate,  and  sometimes  exophthalmos 
and  dilatation  of  the  pupil.  Similar  effects  are  to  be  seen  in 
exophthalmic  goiter,  and  some  of  them  suggest  stimulation  of 
the  sympathetic  nervous  system.  In  monkeys  Edmunds  found 
that  death  occurred  from  asthenia. 

Therapeutics. — (1)  In  Myxedema  and  Cretinism. — In  these 
conditions  the  effects  are  most  striking.  In  myxedema  the 
mentality  and  the  physical  characteristics  are  restored;  in  creti- 
nism the  patient  may  be  changed  from  a  maldeveloped  and 
hopelessly  idiotic  child  to  a  well-developed  and  more  intelligent 
one. 

(2)  After  thyroidectomy — to  prevent  the  usual  train  of  symp- 
toms.   It  is  effective  if  the  parathyroids  have  not  been  removed. 

(3)  In  hypothyroidism,  as  after  some  partial  thyroidectomies, 
and  in  the  late  stages  of  exophthalmic  goiter  where  reversion 


522  PHARMACOLOGY  AND  THERAPEUTICS 

to  colloid  has  taken  place.  It  is  believed  that  there  are  many- 
cases  of  hypothyroidism,  with  ill-defined  symptoms,  in  which 
thyroid  may  be  of  benefit;  but  the  distinguishing  features  of 
this  condition  have  not  been  satisfactorily  determined. 

(4)  In  Colloid  Goiter.  (5)  In  Obesity.  (6)  In  Rheumatoid 
Arthritis.  (7)  In  Infantile  Wasting.  (8)  In  Osteomalacia,  Rickets, 
and  Delayed  Union  of  Fractures. 

It  is  contraindicated  in  the  hyperplasia  stage  of  exophthalmic 
goiter,  as  it  increases  the  symptoms.  (For  recent  reviews  on 
thyroid,  see  books  on  Internal  Secretions  by  Swale  Vincent  and 
Biedl.) 

Antithyroid  Preparations 

There  are  several  preparations  on  the  market  designed  to 
overcome  thyroid  hyperactivity.    The  best  known  are: 

Beebe's  serum,  a  serum  obtained  from  thyroidectomized 
animals. 

Antithyroidin  (Moebius)  the  blood-serum  obtained  from  sheep 
whose  thyroid  glands  had  been  removed  at  least  six  weeks 
before.  It  is  preserved  with  0.5  per  cent,  of  phenol,  and  is  given 
by  mouth  in  dose  of  8  to  15  minims  (0.5-1  c.c.)  three  times 
a  day. 

Thyreoidectin,  consisting  of  gelatin  capsules  each  containing 
5  grains  (0.3  gm.)  of  a  powder  prepared  from  the  dried  blood  of 
thyroidectomized  animals.  Dose,  one  or  two  capsules  three 
times  a  day. 

EXPECTORANTS 

Expectorants  tend  to  fluidify,  consequently  to  promote  the 
flow  of,  respiratory  mucus.  Their  action  is  directly  opposed  by 
belladonna.  Most  of  them  act  reflexly  from  an  irritant  (nauseant) 
action  in  the  stomach.  Henderson  and  Taylor  (191  o)  showed 
this  to  be  the  case  with  ammonium  compounds,  antimony, 
ipecac,  and  senega.  We  have  considered  the  ammonium  salts, 
iodide,  antimony,  and  pilocarpine.  Others  in  common  use  are: 
Ipecac,  1  grain  (0.06  gm.),  senega,  15  grains  (1  gm.),  and  aspido- 
sperma  (quebracho),  30  grains  (2  gm.).  In  a  test-tube  the 
alkalies  liquefy  mucus  but  when  given  by  mouth,  probably 
have  no  effect  in  the  bronchi. 

Certain  bronchial  antiseptics  have  been  mentioned  under 
Antiseptics.  Whether  or  not  they  act  as  true  expectorants  is 
a  question;  and  whether  they  are  eliminated  in  the  bronchial 
mucus  in  sufficient  quantity  to  stimulate  the  mucous  membrane 
or  to  act  as  antiseptics  has  not  been  proved.    They  are :  Certain 


IPECACUANHA  523 

volatile  oil  drugs,  as  oil  of  turpentine,  terebene,  pine  needle  oil, 
tar,  creosote,  camphor,  cubebs,  and  garlic,  dose,  5  minims 
(0.3  c.c.)  or  5  grains  (0.3  gm.) ;  also  terpin  hydrate,  dose,  5  grains 
(0.3  gm.),  benzoic  [acid,  benzoin,  balsam  of  Tolu,  and  balsam  of 
Peru. 

In  some  cases  bronchial  activity  is  promoted  by  the  tonic 
action  of  such  a  drug  as  strychnine. 

Favorite  expectorant  mixtures  are : 

1.  The  compound  licorice  mixture,  brown  mixture  (not 
Brown's  Mixture),  which  contains  licorice,  paregoric,  wine  of 
antimony,  and  spirit  of  nitrous  ether.  Dose,  1  dram  (4  c.c).  It 
is  not  a  very  effective  expectorant. 

2.  The  compound  syrup  of  squill  (Coxe's  hive  syrup),  which 
contains  8  parts  each  of  the  fluidextracts  of  squill  and  senega, 
and  0.2  part  of  tartar  emetic  per  100.  Dose,  %  dram  (2  c.c.) 
every  two  or  three  hours. 

3.  Mistura  pectoralis,  N.  F.  (Stokes'  mixture),  containing 
ammonium  carbonate,  8  grains  (0.5  gm.),  the  fluidextracts  of 
senega  and  squill,  each,  15  minims  (1  c.c),  paregoric,  75  minims 
(5  c.c)  in  each  ounce  (30  c.c),  with  syrup  of  Tolu.  Dose,  1 
dram  (4  c.c.)  every  two  or  three  hours. 

Therapeutics. — To  promote  the  flow  of  mucus  and  lessen 
congestion  in  the  respiratory  tract,  particularly  in  the  dry  stages 
of  bronchial,  nasal,  or  laryngeal  inflammation. 


IPECACUANHA 

Ipecac   (ipecacuanha)  is  the  root  of  Cephaelis  Ipecacuanha 
from   Brazil,  and  of  the  Carthagena  ipecac,  Cephaelis  acuminata 
(Fam.  Rubiacece),  and  it  is  required  to  yield  on  assay  not  less 
than  2  per  cent,  of  alkaloid.     It  contains  3  alkaloids — emetine, 
the  important  one,  and  cephaeline  and  psychotrine. 
Preparations  and  Doses. — The  expectorant  dose  is: 
Ipecac,  1  grain  (0.06  gm.). 
Fluidextract,  1  minim  (0.06  c.c). 
Syrup,  7  per  cent,   (acid  with  acetic  acid),   15  minims 

(1  c.c). 
Wine,  10  per  cent.,  10  minims  (0.6  c.c). 
Powder  of  ipecac  and  opium,   10   per    cent.,    10   grains 

(0.6  gm.). 
Tincture  of  ipecac  and  opium,  10  per  cent.,   10  minims 
(0.6   c.c). 
The  emetic  dose  is  15  grains  (1  gm.).     The  dose  in  amebic 
colitis  is  30  grains  (2  gm.),  given  in  enteric  pills  to  prevent 
vomiting. 


524  PHARMACOLOGY  AND  THERAPEUTICS 

Emetine  chloride  is  used  in  amebic  colitis  in  dose  of  2  grains 
(0.13  gm.). 

Pharmacologic  Action. — Locally  ipecac  is  irritant.  Applied 
to  the  skin  in  paste  form,  it  will  produce  a  pustular  rash. 

Alimentary  Tract. — When  the  drug  is  swallowed,  it  irritates 
the  stomach  and  tends  to  produce  nausea  and  vomiting.  From 
an  emetic  dose  the  nausea  comes  on  at  once,  and  after  more  or 
less  delay  is  followed  by  vomiting.  The  nausea  and  vomiting 
are  due  to  local  irritation,  and  not  to  any  direct  effect  upon  the 
vomiting  center.  For  if  the  dose  is  preceded  by  a  large  dose 
(1  dram)  of  bismuth  subnitrate  or  cerium  oxalate,  vomiting 
does  not  ensue;  and  if  it  is  given  subcutaneously,  vomiting  is 
slow  in  its  onset  and  the  dose  must  be  large.  The  vomiting 
comes  on  only  when  the  drug  is  excreted  into  the  stomach,  and 
it  may  follow  doses  given  subcutaneously  or  in  enteric  pills. 
The  usual  accompaniments  of  nausea  are:  rapid  pulse,  sweating, 
salivation,  free  flow  of  mucus,  especially  in  the  respiratory  pas- 
sages, general  weakness  and  perhaps  diarrhea. 

Ipecac  is  said  to  raise  arterial  pressure  by  peripheral  vaso- 
constriction (Dixon),  but  accompanying  the  nausea  there  is  a 
fall  in  pressure.  Large  doses  give  the  poisonous  symptoms  of 
an  irritant  drug.  If  prompt  vomiting  does  not  take  place,  there 
are  diarrhea,  abdominal  cramps,  bloody  stools,  collapse,  and 
possibly  acute  nephritis. 

Ipecac  promotes  secretion,  especially  that  of  the  skin  and 
of  the  respiratory  tract. 

Therapeutics. — 1.  As  diaphoretic  in  the  form  of  Dover's 
powder,  with  plenty  of  hot  liquid  to  drink. 

2.  As  expectorant  in  dry  bronchitis,  laryngitis,  and  rhinitis. 

3.  As  nauseant  or  emetic  in  non-diphtheric  croup. 

4.  In  amebic  dysentery — in  this  condition  ipecac  is  believed 
by  many  to  be  specific.  It  is  employed  very  extensively  in  the 
Philippines.  Formerly  the  emetic  effect  largely  barred  its  use- 
fulness; but  it  is  now  given  in  "enteric"  pills,  a  sufficient  number 
to  give  a  dose  of  30  grains  (2  gm.)  of  ipecac  being  administered 
at  the  outset,  and  repeated  daily  for  several  days.  Sometimes 
the  patients  escape  vomiting,  but  often  they  are  nauseated. 
Emetine  chloride  has  also  been  employed  by  mouth  in  doses 
of  2  grains  (0.13  gm.),  and  hypodermatically  in  dose  of  j4  to 
3 4  grain  (0.03-0.045  gm.).  Rogers  believes  that  the  ipecac 
treatment  will  not  only  cure  the  colitis,  but  will  check  amebic 
hepatitis  and  prevent  the  formation  of  a  liver  abscess.  He  also 
advises  it  following  operations  for  abscess.  Deemetinized  ipecac, 
which  is  not  emetic,  is  useless  in  amebic  colitis. 


ERGOT  525 

EMMENAGOGUES 

These  are  remedies  which  tend  to  bring  on  the  menstrual 
flow.     They  are: 

1 .  Local  measures,  as  hot  or  mustard  foot-  or  sitz-baths,  hot- 
water  bottle  or  counterirritant  (turpentine,  mustard)  to  lower 
abdomen,  hot  vaginal  douches. 

2.  Strong  purgatives,  as  aloes,  jalap,  castor  oil. 

3.  Genito-urinary  irritants,  as  cantharis,  caulophyllum  (blue 
cohosh). 

4.  Drugs  which  stimulate  the  uterine  muscle,  as  ergot,  hydrastis, 
quinine  (corn-smut  and  cotton-root  bark).     . 

5.  Measures  to  improve  the  general  health,  as  iron,  cod-liver 
oil,  strychnine;  in  heart  disease,  digitalis;  in  tuberculosis,  dry 
cool  air. 

In  early  pregnancy  any  of  these  measures  except  those  of 
the  last  group  may  result  in  abortion,  so  an  emmenagogue  is 
also  an  abortifacient. 


ERGOT 

Ergot  (ergota)  is  a  fungus  which  replaces  the  grain  of  rye. 
It  rapidly  deteriorates  and  should  not  be  more  than  one  year 
old.    Our  supply  comes  from  Europe. 

Constituents. — Though  a  vast  amount  of  study  was  given 
to  ergot  for  many  years,  its  chemistry  remained  in  a  state  of 
great  confusion  until  Dale  and  his  associates  published  their 
admirable  studies  in  1909  and  1910.  We  now  recognize  two  very 
active  alkaloids,  ergotoxine  and  tyramine,  and  two  unimportant 
ones,  ergotine  and  isoamylamine.  In  addition  there  may  be 
choline,  and  there  are  ergotinic  acid,  various  saponins,  and  20 
to  35  per  cent,  of  fat. 

Ergotoxine  is  a  hydrated  ergotine.  It  is  almost  insoluble 
in  water,  but  is  soluble  in  alcohol.  Its  phosphate,  which  is 
soluble  in  water,  is  employed. 

Tyramine  is  readily  soluble  in  water.  It  is  para-hydroxy- 
phenyl-ethylamine,  and  is  closely  related  to  certain  amines  found 
in  unpurified  cod-liver  oil  as  the  result  of  the  putrefaction  of  the 
cod-livers.  It  also  bears  a  somewhat  close  chemical  relation  to 
epinephrine.  It  may  be  formed  by  the  prolonged  trypsin  diges- 
tion of  egg-albumin  (Langestein,  1902),  and  was  obtained  by 
the  action  of  a  culture  of  human  feces  on  broth  to  winch  tyrosin 
was  added  (Barger  and  Walpole,  1909);  hence  it  is  probably  a 
product  of  intestinal  putrefaction  in  some  human  cases.  It  has 
also  been  prepared  synthetically. 


526 


PHARMACOLOGY   AND   THERAPEUTICS 


Preparations  and  Doses. — 

Ergot,  30  grains  (2  gm.). 
Fluidextract  (acetic),  30  minims  (2  c.c). 
Extract,  4  grains  (0.25  gm.). 
Wine,  2  drams  (8  c.c). 

All  galenical  preparations  of  ergot  rap- 
idly deteriorate,  but  the  fluidextract  is  as 
good  as,  and  in  many  cases  better  than,  any 
of  the  many  proprietaries  upon  the  market 
(Edmunds  and  Hale,  191 1). 

The  alkaloids  also  may  be  employed — er- 
go toxine  phosphate  in  dose  of  -^  grain  (0.0012 
gm.),  and  tyr amine  in  dose  of  }4  grain  (0.03 
gm.)  hypodermatically.  They  are  not  irri- 
tant. 

Standardization. — Up  to  the  present  no 
chemic  assay  has  proved  satisfactory.  For 
the  physiologic  assay  three  chief  methods 
have  been  employed,  viz.,  the  blood-pressure 
method,  the  uterine  method,  and  the  cocks- 
comb method.  The  first  is  not  good,  the 
pressor  effect  giving  no  indication  of  the  con- 
tractile power  of  the  drug  upon  the  uterus. 
The  uterine  method  is  satisfactory,  but  is  ex- 
pensive and  tedious.  Edmunds  and  Hale 
and  a  number  of  others  recommend  the 
cockscomb  method.  This  is  based  on  the  de- 
velopment of  a  purple  hue  in  the  comb  of  a 
rooster  from  an  injection  of  ergot.  The 
standard  is  considered  to  be  0.75  c.c.  of  fluid- 
extract  per  kilo,  equivalent  to  1.87  mg.  of 
ergotoxine  phosphate. 

Deterioration. — Ergot  rapidly  deteriorates 
unless  kept  from  the  air,  and  a  number  of 
investigators  report  that  ergot  and  ergot 
preparations  are  useless  if  more  than  a  year 
old.  Yet  this  is  not  found  to  be  the  case  in 
clinical  experience,  which  corresponds  more 
nearly  with  the  experimental  work  of  Has- 
kell and  Eckler  (191 2).  They  tested  sepa- 
rately, and  then  mixed  together,  a  large  number  of  fluidextracts 
made  in  the  different  years.  Those  one  and  two  years  old  gave 
a  reaction  in  the  standard  amount,  i.  e.,  0.75  c.c.  per  kilo.  Those 
three  years  old  required  1  c.c.  for  the  reaction,  those  four  years 
old  1.5  c.c,  and  those  five  years  old  1.75  c.c. 


Fig.    60. — Ergotized 
rye  (Maisch). 


ERGOT  527 

Pharmacologic  Action. — The  active  principles  of  ergot  stimu- 
late the  ends  of  certain  sympathetic  nerves  or  their  myoneural 
junctions.  In  large  amounts  ergotoxine  paralyzes  the  same 
endings. 

Local. — Ergot  is  irritant  to  mucous  membranes  and  raw 
tissues.  It  has  practically  no  constricting  action  on  mucous 
membranes,  but  when  injected  hypodermatically  produces  a 
moderate  constriction  of  the  arteries  at  the  point  of  injection. 
In  some  cases  it  has  caused  local  gangrene. 

Alimentary  Tract. — Preparations  of  ergot  are  irritant  locally 
and  may  cause  nausea,  or,  in  poisoning,  a  violent  gastro-enteritis. 
The  alkaloids  are  not  irritant.  Therapeutic  doses  of  ergot  stimu- 
late the  ends  of  the  splanchnic  (inhibitory)  nerves,  and  cause 
decreased  intestinal  peristalsis.  Very  large  doses  cause  paralysis 
of  the  same  sympathetic  nerve-endings,  and  result  in  increased 
peristalsis  and  activity  of  the  bowels.  This  effect  is  not  obtain- 
able in  therapeutics.  In  testing  roosters  it  is  usual  for  their 
bowels  to  move. 

Arteries. — Ergotoxine  or  tyramine,  injected  intravenously, 
will  cause  an  abrupt  rise  in  arterial  pressure  similar  to  that  from 
epinephrine.  But  the  rise  in  pressure  is  slower.  Its  duration 
is  three  or  four  times  as  long,  and  it  results  from  mouth  and 
hypodermic  doses  as  well  as  from  intravenous  (Dale).  The 
constriction  of  the  arteries  at  the  site  of  injection  is  much  less 
than  that  from  epinephrine,  but  it  lasts  longer  and  in  a  number 
of  instances  has  resulted  in  local  gangrene. 

The  action  is  a  peripheral  one,  for  it  occurs  after  section  of 
the  splanchnic  nerves,  and  on  perfusion  of  a  viscus  or  limb. 
There  is  no  constriction  on  perfusing  the  pulmonary  arteries, 
hence  the  action  is  not  on  the  arterial  muscle.  It  seems  to  be 
on  the  myoneural  junctions  of  the  vasoconstrictor  nerves. 

If  a  large  dose  of  ergotoxine  is  given,  these  vasoconstrictor 
nerve-terminals  become  paralyzed.  But  there  is  apparently  no 
effect  on  the  vasodilators,  so  that,  if  the  dose  of  ergotoxine  is 
followed  by  epinephrine  or  nicotine,  the  arteries,  instead  of  con- 
tracting, dilate  and  cause  a  fall  of  arterial  pressure.  This  is  the 
"vasomotor  reversal"  of  Dale. 

Heart. — From  large  doses  the  isolated  heart  is  increased  in 
strength  and  rate;  but  in  situ  the  heart  may  slow  as  a  result  of 
the  high  blood-pressure. 

Arterial  Pressure. — Tests  with  tyramine  on  human  blood- 
pressure  have  been  made  by  Dale  and  Dixon  (iqio-iqii),  Clark 
(191 1),  and  Hoyt  (191 2).  Ten  milligrams  by  mouth  and  doses 
of  5  mg.  and  10  mg.  three  times  a  day,  had  no  effect  (Hoyt),  and 
100  mg.  by  mouth,  repeated  in  forty  minutes,  was  also  without 


528  PHARMACOLOGY  AND  THERAPEUTICS 

effect  (Clark).  Hypodermatically,  doses  of  more  than  20  mg. 
are  required  (Hoyt,  Clark).  After  40  mg.  by  hypodermatic  in  a 
patient  with  myocarditis,  the  pressure  rose  from  85  to  130  mm. 
in  five  minutes,  and  had  returned  to  normal  at  the  end  of  nine- 
teen minutes  (Hoyt).    This  is  like  a  retarded  adrenaline  action. 

Though  the  action  of  the  active  principles  is,  therefore,  well 
known,  the  effect  of  preparations  of  ergot  itself  upon  the  circula- 
tion is  problematic.  For,  given  intravenously,  ergot  may  induce 
a  fall  in  pressure,  as  Sollmann  and  Brown  (1905)  found  in  350 
experiments  on  38  animals;  or  it  may  cause  a  striking  rise  in 
pressure.  The  fall  in  pressure  is  attributed  to  the  saponin  bodies. 
In  therapeutics,  it  is  hardly  possible  to  give  enough  ergot  to 
obtain  a  rise  in  pressure,  but  a  hypodermatic  or  intravenous  of 
tyramine  is  a  practical  method  of  raising  the  arterial  tension  in 
emergency. 

Respiration. — After  the  intravenous  injection  of  0.001  gm. 
per  kilo  of  ergotoxine,  the  respiratory  center  is  depressed,  as 
shown  by  slow  and  shallow  breathing  or  Cheyne-Stokes  respira- 
tion (Wiggers). 

Uterus. — To  a  slight  degree  through  a  central  action,  but 
essentially  through  stimulation  of  the  myoneural  junctions  of  the 
hypogastric  nerves  with  the  uterus,  uterine  contraction  is  pro- 
moted. In  the  early  stages  of  pregnancy  the  increase  may  be 
seen  in  the  strengthening  of  the  normal  intermittent  contrac- 
tions which  take  place  at  this  time;  and  there  is  a  prevalent 
belief  both  in  the  profession  and  among  the  laity  that  in  the  early 
months  of  pregnancy  ergot  is  abortifacient.  But  experiments 
with  pregnant  animals  have  not  shown  it  to  possess  this  power 
to  any  great  degree;  and  in  pregnant  women,  it  has  very  fre- 
quently failed  to  have  the  slightest  effect.  It  is  of  considerable 
interest  that  in  some  cases  of  ergotism  pregnancy  has  gone  on  to 
term  without  interruption. 

In  labor,  moderate  doses  tend  to  increase  the  strength  of  the 
normal  intermittent  contractions,  while  large  doses  (1  dram — 
4  gm.)  produce  a  continuous  or  tetanic  contraction  of  the  uterus. 
This  makes  ergot  of  value  after  labor  to  promote  the  normal 
postpartum  uterine  contraction;  but  it  should  not  be  adminis- 
tered until  the  uterus  is  empty,  lest  the  organ  go  into  tetanic 
contraction  and  compress  the  contents  without  expelling  them. 
The  drug  usually  takes  thirty  to  sixty  minutes  to  act  when  given 
by  mouth. 

The  stoppage  of  uterine  hemorrhage  is  essentially  due  to 
the  uterine  contraction,  and  is  not  to  any  great  degree,  if  at  all, 
attributable  to  contraction  of  the  uterine  arteries. 

Toxicology. — Acute  poisoning  is  usually  the  result  of  large 


ERGOT  529 

doses  taken  to  produce  abortion.  The  symptoms  are — (1) 
those  of  gastro-enteritis,  with  nausea,  vomiting-,  diarrhea,  and 
abdominal  pain,  and  (2)  various  nervous  manifestations,  such 
as  itching,  tingling,  hyperesthesia,  and  anesthesia  of  the  skin, 
mental  depression,  convulsions,  coma,  and  collapse.  The  treat- 
ment is  symptomatic  for  gastro-enteritis  and  collapse. 

Chronic  Poisoning  or  Ergotism. — This  is  not  seen  in  this 
country,  though  it  has  been  in  the  past  common  enough  in  Europe 
from  the  consumption  of  bread  made  from  ergot-infected  rye. 
The  ergotism  manifests  itself  either  by  gangrene  or  by  certain 
pronounced  nervous  symptoms.  The  gangrene  is  caused  by 
persistent  contraction  of  the  arteries  in  some  particular  part  of 
the  body,  chiefly  the  fingers,  toes,  ears,  and  tip  of  the  nose.  But 
there  may  be  sloughing  in  any  part  of  the  body  surface,  or  ulcer 
of  the  stomach,  or  even  gangrene  of  the  lung  or  of  the  uterus. 
The  small  arteries  of  the  part  are  found  to  contain  hyaline  plugs, 
as  in  any  case  of  dry  gangrene.  The  nervous  type  shows  in  gastro- 
intestinal disturbances,  itching  of  the  skin,  headache,  dizziness, 
disordered  vision,  temporary  or  permanent  blindness,  drowsiness, 
mental  depression,  and  clonic  or  epileptiform  convulsions  which 
may  leave  permanent  contractures  in  hands,  feet,  arms,  legs,  or 
trunk.  These  manifestations  are  thought  to  be  due  to  spasm 
in  the  arteries  of  the  central  nervous  system;  the  permanent 
effects  are  due  to  softening  from  the  shutting  off  of  the  arteries. 

Therapeutics. — The  main  employment  of  ergot  is — (1)  To 
prevent  postpartum  hemorrhage,  which  it  does  by  inducing  uterine 
contraction  rather  than  by  narrowing  the  vessels;  (2)  to  check 
menorrhagia,  and  (3)  to  overcome  subinvolution  of  the  uterus. 
Though  it  has  been  used  for  hemorrhage  from  stomach,  lungs, 
kidneys,  etc.,  there  is  no  indication  that  a  therapeutic  dose  pro- 
duces constriction  of  the  arteries  in  these  regions.  In  any  dose 
whatever  it  does  not  constrict  the  pulmonary  arteries. 

It  has  been  employed  to  raise  blood-pressure,  but  for  this 
purpose,  as  we  have  seen,  the  active  principles  are  to  be  used, 
and  not  ergot  itself.  Thus  tyramine  might  be  employed  in  shock 
or  collapse.  To  obtain  arterial  constriction,  Wiggers  used  -^5- 
grain  (0.001  gm.)  of  ergotoxine  phosphate  per  kilo  in  dogs.  He 
advised  that  the  dose  should  not  be  repeated,  as  the  paralysis 
of  the  nerve-endings  might  come  on. 

On  empirical  grounds  ergot  has  been  proposed  for  a  great 
many  different  conditions;  for  example,  it  is  spoken  highly  of  in 
diabetes  insipidus,  enuresis  nocturna,  and  delirium  tremens. 
The  author  found  it  useless  in  diabetes  mellitus  and  the  night- 
sweats  of  tuberculosis.  Ransom  speaks  highly  of  it  in  delirium 
tremens.  (See  Alcohol.) 
34 


530  PHARMACOLOGY   AND    THERAPEUTICS 

Ergotoxine  is  employed  in  physiologic  experimentation  to 
paralyze  sympathetic  nerve-endings,  especially  the  vasocon- 
strictors. 

HYDRASTIS 

Hydrastis,  or  goldenseal,  is  the  dried  rhizome  and  roots 
of  Hydrastis  canadensis  (Fam.  Ranunculacece) ,  yielding,  when 
assayed,  not  less  than  2.5  per  cent,  of  hydrastine.  It  is  a  small 
herb  of  the  eastern  United  States. 

Constituents. — Three  alkaloids:  hydrastine,  2.5  per  cent.; 
berberine,  3  to  4  per  cent.,  and  a  little  canadine;  in  addition, 
some  resinous  material. 

Preparations. — Hydrastis,  30  grains  (2  gm.).  Fluidextract  (2 
per  cent,  hydrastine),  30  minims  (2  c.c).  Glycerite,  100  per 
cent.,  30  minims  (2  c.c).  Tincture,  20  per  cent.,  1  dram  (4  c.c). 
Hydrastine,  the  alkaloid,  %  grain  (0.01  gm.). 

Pharmacologic  Action. — Local. — It  has  a  slightly  astringent 
action,  and  in  some  sections  is  employed  as  a  stimulant  of  mucous 
membranes  in  chronic  catarrhal  conditions,  as  of  nose,  throat, 
urethra,  and  vagina. 

Alimentary  Tract. — It  has  a  bitter  effect  upon  appetite. 
Through  a  central  action  it  increases  the  motor  and  secretory 
activity  of  the  stomach  and  promotes  intestinal  peristalsis. 
Large  doses  cause  vomiting  and  diarrhea. 

Nervous  System. — On  the  medulla  and  cord  hydrastine  acts 
like  strychnine,  stimulating  the  respiratory,  vagus,  and  vaso- 
constrictor centers  and  increasing  reflex  irritability.  It  is,  there- 
fore, a  true  tonic  Very  large  doses  cause  tonic  and  clonic  con- 
vulsions, incoordination,  and  depression  of  the  medullary  centers. 

Eye. — Locally  applied,  it  first  contracts  then  dilates  the  pupil. 

Circulation. — The  heart  is  slowed  through  vagus  center  stimu- 
lation, the  muscle  being  slightly  stimulated  directly.  The  arteri- 
oles are  contracted  through  the  vasoconstrictor  center. 

In  poisoning  the  centers  are  depressed,  and  the  heart  becomes 
slow  and  feeble  from  direct  action  on  the  cardiac  muscle.  At  the 
same  time  the  muscles  in  the  arterioles  become  depressed  and  the 
vessels  dilate;  hence  blood-pressure  is  very  low.  It  is  said  to 
differ  materially  from  strychnine,  as  this  tendency  to  depress 
the  heart  is  manifested  before  convulsions  come  on. 

Respiratory. — Ordinarily,  the  respiratory  center  is  stimulated; 
but  in  poisoning  it  is  depressed,  and  death  takes  place  from  as- 
phyxia brought  on  by  paralysis  of  the  respiratory  center  or  by 
the  convulsions. 

Muscle. — Muscular  tissue  of  all  kinds  (except  perhaps  the 
uterus)  is  primarily  stimulated,  then  depressed. 


HYDRASTININE   CHLORIDE  531 

Uterus. — Hydrastis  resembles  ergot  in  its  tendency  to  in- 
crease the  normal  contraction  of  the  uterus,  but  it  is  much  less 
powerful  in  bringing  about  contraction  of  the  postpartum  uterus. 
In  menorrhagia  or  metrorrhagia  from  fibroids,  subinvolution,  or 
relaxed  uterus,  it  may  arrest  hemorrhage  both  by  uterine  stimu- 
lation and  by  cutting  off  the  uterine  blood-supply.  In  other 
parts  of  the  body  such  an  effect  in  stopping  hemorrhage  seems 
to  be  counteracted  by  the  rise  in  blood-pressure.  The  uterine 
effect  is  due  to  both  the  hydrastine  and  the  berberine. 

Elimination. — Hydrastine  is  excreted  in  the  urine  as  such, 
no  hydrastinine  being  formed  in  the  body.  Slight  amounts  also 
appear  in  the  saliva  and  feces. 

Therapeutics. — Hydrastis  has  been  much  employed  locally 
in  chronic  catarrh  of  nose,  throat,  urethra,  and  vagina.  Owing 
to  the  large  amounts  of  bitter  alkaloids,  it  is  a  powerful  bitter. 
It  is  also  employed  in  postpartum  hemorrhage,  subinvolution, 
menorrhagia,  and  metrorrhagia,  whether  caused  by  fibroids  or 
not. 

HYDRASTININE  CHLORIDE 

This  salt  (hydrastinince  chloridum),  CuHiiN02.HCl,  is  the 
chloride  of  an  artificial  alkaloid  formed  by  the  oxidation  of 
hydrastine.  Dose,  y2  grain  (0.03  gm.).  It  is  freely  soluble  in 
water  and  alcohol.  Hydrastinine  has  a  local  constricting  effect 
on  arteries,  and  has  the  same  action  on  centers  as  hydrastine; 
but  it  has  little  if  any  effect  in  depressing  the  heart  and  other 
muscles.  It  induces  a  rise  in  blood-pressure  through  stimulation 
of  the  vasoconstrictor  center.  It  causes  rapid  dilatation  of  the 
pupil,  the  effect  wearing  off  inside  of  twenty-four  hours. 

It  is  for  its  action  on  the  uterus,  however,  that  hydrastinine 
is  employed,  as  it  tends  to  stop  hemorrhage  by  cutting  down 
the  blood-supply  of  the  uterus  through  arteriole  constriction, 
and  to  a  moderate  degree  by  stimulating  the  uterus  itself.  It 
is  not  so  good  as  ergot  in  postpartum  hemorrhage,  but  is  largely 
employed  in  subinvolution,  in  late  hemorrhage  following  par- 
turition, and  in  profuse  menstruation,  whether  caused  by  fibroids 
or  not.  A  10  per  cent,  solution  has  been  employed  locally  on 
cotton  in  hemorrhage  from  nose,  mouth,  rectum,  and  uterus. 

Cotarnine  chloride,  stypticin,  is  not  official,  and  is  oxymethyl 
hydrastinine;  dose,  }4  grain  (0.03  gm.).  It  is  prepared  from 
narcotine,  and  has  an  action  practically  like  that  of  hydrastinine, 
but  with  a  hydrastine  tendency  to  depress  the  heart  muscles. 
Its  uses  are  those  of  hydrastinine. 


532  PHARMACOLOGY   AND   THERAPEUTICS 

CARBON  MONOXIDE 

This  gas  (CO)  becomes  of  interest  from  the  frequency  of  its 
poisoning.  Most  of  the  cases  result  from  illuminating-gas, 
which  contains  6  to  10  per  cent.,  and  is  frequently  inhaled  with 
suicidal  intent.  But  some  come  from  defective  flues  of  furnaces, 
coal  stoves,  charcoal  fires,  blast  furnaces,  and  the  "after-damp" 
of  mines  and  old  wells. 

The  gas  has  great  affinity  for  hemoglobin,  and  prevents 
the  formation  of  oxyhemoglobin  unless  oxygen  is  present  in  very 
great  excess.  But  the  compound  is  not  a  very  stable  one  and 
usually,  if  respiration  is  good  and  oxygen  plentiful,  splits  up  so 
that  all  the  carbon  monoxide  will  be  exhaled  by  the  lungs  in  from 
one  to  three  hours.  The  monoxide  does  not  oxidize  to  carbon 
dioxide  in  the  body. 

The  action  of  the  gas  is  asphyxia!,  the  exclusion  of  oxygen 
from  the  tissues,  particularly  the  central  nervous  system,  being 
the  cause  of  the  symptoms.  Haldane  found  that  when  mice 
were  placed  in  oxygen  under  two  atmospheres  pressure,  so  that 
the  plasma  would  carry  enough  oxygen  to  maintain  life,  carbon 
monoxide  had  no  toxic  effect ;  but  that  when  the  oxygen  pressure 
was  removed  by  exposing  the  mice  to  the  air,  poisoning  followed. 
The  toxic  symptoms  are,  therefore,  due  to  an  interference  with 
the  oxygen-carrying  power  of  the  blood. 

The  symptoms  are  those  of  stimulation  of  the  cerebrum  and 
medullary  centers,  followed  by  their  depression.  At  first  there 
are  headache,  dizziness,  mental  excitement  or  delirium,  slow 
pulse  from  stimulation  of  the  vagus  center,  raised  arterial  pres- 
sure from  stimulation  of  the  vasoconstrictor  center,  dyspnea  from 
stimulation  of  the  respiratory  center,  and  nausea  and  vomiting 
from  stimulation  of  the  vomiting  center.  These  may  be  fol- 
lowed by  mental  dulness  or  coma,  prostration,  rapid  weak  pulse, 
lowered  blood-pressure,  slow  and  shallow  or  Cheyne-Stokes 
respiration,  fever,  loss  of  control  of  the  sphincters,  and  convul- 
sions, usually  of  cerebral  (epileptiform)  type.  The  heart  con- 
tinues to  beat  after  respiration  has  ceased.  In  the  late  stages 
there  is  sometimes  great  spasticity  or  muscular  rigidity,  so  that 
the  patient  seems  as  ''stiff  as  a  board."  Spiller  and  others  find 
this  associated  with  bilateral  softening  of  the  inner  segments  of 
the  lenticular  nuclei,  the  softening  being  due  to  changes  in  the 
minute  supplying  arteries. 

A  striking  characteristic  of  the  poisoning  is  a  subsidence  of 
the  acute  symptoms,  followed  by  apparent  recovery,  and  then 
some  hours  or  days  later  the  appearance  of  serious  disturbances 
of  the  central  nervous  system,  showing  in  mental  derangement, 
paralyses,  epileptiform  convulsions,  or  collapse  and  death. 


CARBON   MONOXIDE  533 

Acute  poisoning  is  divided  by  McComb  (191 2),  who  has  seen 
1000  cases,  into  three  stages,  viz. : 

1.  Before  the  patient  loses  consciousness.  It  is  the  stage  of 
stimulation. 

2.  After  the  patient  loses  consciousness,  respiration  still  per- 
sisting. This  is  the  stage  of  depression.  In  this  stage  or  later, 
cherry-red  spots  over  the  cheek-bones,  neck,  trunk,  and  thighs 
may  make  their  appearance,  and  there  may  be  petechiae. 

3.  Patient  unconscious,  no  spontaneous  respiration.  The 
heart  is  rapid,  weak,  intermittent. 

Chronic  poisoning,  as  from  daily  exposure  over  long  periods, 
shows  in  nausea,  headache,  dizziness,  mental  depression,  lassi- 
tude, loss  of  appetite  and  of  flesh  and  strength,  and  gastric  dis- 
turbances. It  may  give  any  of  the  symptoms  of  the  first  stage 
of  acute  poisoning.  McCombs,  who  has  studied  the  men  of  gas 
companies,  reports  polycythemia  as  quite  common,  and  calls 
attention  to  the  fact  that  there  are  many  men  who  have  been 
much  exposed  to  the  gas  for  many  years  without  any  special 
sign  of  ill  health. 

Treatment. — 1.  Of  first  importance  in  the  mild  poisoning  is 
fresh  air,  and  in  the  severe  degrees,  oxygen,  under  pressure,  if 
possible. 

2.  Artificial  respiration,  deep  breathing  being  essential  to  the 
elimination  of  the  gas. 

3.  Maintenance  of  body  warmth. 

4.  For  the  nausea  of  the  mild  type  effervescing  drinks,  and 
for  the  headache  a  carminative,  such  as  aromatic  spirit  of  am- 
monia. 

5.  Saline  infusion  after  a  preliminary  blood-letting. 

6.  Transfusion  of  blood  after  a  preliminary  blood-letting. 
This  last  is  the  method  recommended  by  Crile  and  Lenhart, 

and  has  proved  valuable  in  some  cases.  These  investigators 
experimented  on  sixteen  dogs,  giving  carbon  monoxide  until 
respiration  ceased.  Their  results  under  different  treatments 
were  as  follows: 

Number       Number 
of  Animals  Recovered 

(a)  By  manipulation  of  the  heart  and  artificial  respiration 2  o 

(b)  By  manipulation  of   the   heart,  artificial   respiration,  and 

bleeding 1  o 

(c)  By  manipulation  of  the  heart,  artificial  respiration,  bleeding, 

and  saline  infusion 3  o 

(d)  By  manipulation  of  the  heart,  artificial  respiration,  bleeding, 

and  transfusion 10  7 

In  the  cases  in  which  the  heart  had  stopped,  as  well  as  the 
breathing,  transfusion  saved  3  out  of  6. 


534  PHARMACOLOGY  AND  THERAPEUTICS 

OXYGEN 

Oxygen  gas  is  marketed  under  compression  in  steel  containers. 
For  administration  it  is  passed  through  water  in  a  bottle,  and 
conveyed  to  the  patient  by  tubing  terminating  either  in  a  nose- 
piece  to  be  inserted  into  the  nostril,  or  in  a  funnel  to  be  held 
before  the  face.  It  tends  to  dry  the  mucous  membranes,  so  if 
continued  for  any  length  of  time  should  be  accompanied  by  the 
steam  from  a  croup  kettle. 

Action. — The  inhalation  of  oxygen  in  health  has  no  effect 
on  metabolism,  or  on  the  character  or  depth  of  respiration,  but 
it  regularly  reduces  the  rate  of  the  heart  and  tends  to  raise 
arterial  pressure.  Bence  found  that  in  cases  of  cyanosis,  it 
reduced  the  viscosity  of  the  blood;  and  Stewart  noted  that, 
in  a  case  of  emphysema,  chronic  bronchitis,  and  recurring 
cyanosis,  it  increased  the  blood-flow  in  the  hands  from  30  to 
70  per  cent.,  though  it  brought  about  no  especial  changes  in  the 
respiratory  movements. 

The  tension  of  oxygen  in  the  alveolar  air  of  man  is  107  mm. 
Hg  (Starling),  and  at  this  tension  the  oxygen  in  the  hemo- 
globin and  plasma  is  about  15.6  per  cent.  On  breathing  pure 
oxygen  for  a  short  time  the  percentage  rises  to  19.9  per  cent. 
In  cases  of  cyanosis,  however,  where  the  C02  tension  in  the 
blood  is  high,  the  capacity  of  the  blood  for  oxygen  is  diminished. 

Hill  and  Flack  have  noted  that  after  hard  boxing-bouts  of 
men  not  in  good  training,  the  inhalation  of  oxygen  reduced  the 
pulse-rate  almost  to  normal,  abolished  the  shallow,  hurried 
breathing,  and  prevented  the  stiffness  of  the  muscles  which 
otherwise  would  have  followed  on  the  next  day.  It  has  been 
used  in  other  athletic  exercises  with  similar  results. 

In  mountain-climbing,  the  inhalation  of  oxygen  has  proved 
preventive  of  "mountain-sickness,"  which  overcomes  those  not 
inured  to  hard  work  at  high  altitudes. 

Therapeutics. — From  the  physiologic  action,  it  is  evident 
that  the  inhalation  of  oxygen  may  be  of  great  value  in  conditions 
of  cyanosis,  depressed  breathing,  and  failure  of  the  circulation, 
whether  acute  or  chronic.  Its  chief  employment  has  been  in 
pneumonia.  The  author's  method  in  pneumonia  is  to  build 
a  tent  over  the  head  and  shoulders  of  the  patient,  and  let  oxygen 
and  the  steam  from  a  croup-kettle  mingle  with  the  air  in  the  tent. 


PART  III 
PRESCRIPTION  WRITING 

For  three  obvious  reasons  the  writing  of  prescriptions  is  the 
dread  of  the  young  medical  practitioner.     The  reasons  are:    (i) 
His  fear  that  he  may  not  express  his  desires  correctly;    (2)  Ins 
distrust  in  his  ability  to  make  satisfactory  combinations  or 
palatable  mixtures;  and  (3)  his  anxiety  lest  a  faulty  construction 
should  make  him  the  subject  of  the  pharmacist's  criticisms.  >     ^ 
A  prescription  (prce,  scriptum,  written  for)  is  a  physician  s 
order  to  the  pharmacist  directing  him  to  furnish  for  a  patient 
one  or  more  remedies  dispensed  in  some  special  form.     The 
first  essential,  therefore,  in  prescription  writing  is  clearness  of 
meaning,  so  that  the  pharmacist  will,  without  any  doubt,  under- 
stand correctly  the  physician's  desires.     Important  on  the  part 
of  the  physician  is  familiarity  with  weights  and  measures,  the 
symbols  employed  in  prescription-writing,  and,  to  some  extent 
Latin  construction  and  case-endings.     A  table  of  weights  and 
measures  is  to  be  found  in  Part  I.     The  symbols  employed  and 
the  methods  of  expressing  amounts  are  as  follows: 

In  metric  prescriptions  the  amounts  are  expressed  by  simple 
abbreviations  and  Arabic  numerals,  with  fractions  expressed  as 
decimals,  e.  g.,  gm.  6.5,  c.c.  0.6.  In  the  United  States  it  is  under- 
stood that  solids  are  weighed  and  liquids  measured,  so  that  the 
terms  gm.  and  c.c.  may  be  omitted.  An  excellent  way  of  avoid- 
ing the  writing  of  periods,  which  occasionally,  in  hurried  writing, 
may  resemble  the  figure  1,  is  to  draw  a  vertical  fine  and  place  to 
the  left  of  it  all  whole  numbers  referring  to  grams  or  cubic  centi- 
meters, and  to  the  right  of  it  all  fractions.  Thus,  in  the  follow- 
ing formula,  three  ways  of  expressing  the  amounts  are  shown,  viz. : 


06 


I^      Strychnine  sulphatis 0.06  gm.  0.06 

Arseni  trioxidi 0.1    gm.  0.1 

Massae  ferri  carbonatis 8.0    gm.  b.o 

Misce  et  fiant  capsular  No.  xxx. 

In  prescriptions  of  the  apothecaries'  system  the  amounts  are 
expressed  by  certain  special  symbols  and  Roman  numerals. 
The  symbols  commonly  employed  are:  gr.  =  grain  or  grains; 
gtt  =  drop  or  drops;  n\  =  minim  or  minims;  3  =  scruple  or 
scruples;     5  =  dram    or    drams;     5  =  ounce  or    ounces;    lb. 

535 


53^  PHARMACOLOGY   AND   THERAPEUTICS 

=  pound  or  pounds;  O  =  pint  or  pints  (from  octavius.  one- 
eighth  of  a  gallon),  and  Cong.  (Congius)  =  gallon  or  gallons.  As 
solids  are  weighed  and  liquids  measured,  it  is  superfluous  to  pre- 
fix /  before  the  dram  and  ounce  signs,  as  f5,  f  5<  to  indicate  flui- 
dram,  fluidounce.  The  symbol  for  scruple  3  is  dropping  out  of 
use  because  in  written  prescriptions  it  has  frequently  been  mis- 
taken for  3  (dram). 

In  printing  Roman  numerals  of  prescriptions  small  letters 
are  employed  as:  iv  =  4.  xlviii  =  48.  In  writing,  small  letters 
are  used  for  one  (i  or  j),  five  (v),  and  ten  (x),  and  capitals  for  50 
L  .  100  (C),  and  1000  (M);  and  it  is  customary  to  draw  a  line 
above  all  the  letters  making  up  the  number,  the  dots  of  i  and  j 
being  put  above  this  line;  for  example,  xviij.  In  a  number 
with  terminal  one,  as  one,  two,  three,  seven,  or  eight,  the  last 
letter  is  printed  j,  or  written  as  i  with  a  stroke  projecting  below 
the  line,  e.  g.,  ij,  iij,  vij.  This  is  to  signify  that  it  is  terminal. 
Errors  have  been  made  because  of  a  comma  inadvertently  added, 
and  even  because  of  some  mark ,  such  as  a  fly-speck,  upon  the  paper. 
The  dot  over  the  terminal  one  is  an  additional  check;  for  if  all 
the  letters  i  and  j  are  not  dotted,  the  pharmacist  may  be  in  doubt 
as  to  the  number  intended.  As  v,  x,  1  and  c  are  not  dotted  letters, 
it  is  incorrect  to  place  dots  over  them. 

In  expressing  fractions  in  the  apothecaries'  system,  one-half 
is  printed  ss,  and  written  ss  or  fs,  the  manuscript  double  s.  It 
is  an  abbreviation  of  the  Latin  semis.  Other  fractions  are  written 
in  Arabic  numerals  as  vulgar  fractions,  e.  g.,  3-,  J-,  -£-.  Fractions 
other  than  one-half  are  not  employed  with  terms  other  than  grain 
or  minim.  Thus,  while  oiss  is  good  usage,  oi  i  is  not,  and  should 
be  expressed  as  3i  gr.  xii,  or  as  gr.  lxxij. 

A  typical  example  of  an  ordinary  liquid  prescription  is: 

For  Mrs.  Wilson,  April  20,  1913. 

1^      Bismuthi  subnitratis 5ij 

Misturae  cretae q.  s.  ad  3  iij 

M.  et  Sig. —  oij  with  a  little  water  every  three  hours. 

\V.  M.  Johnson,  M.D. 

Interpreted,  this  would  read:  Take  two  drams  of  the  sub- 
nitrate  of  bismuth  and  a  sufficient  quantity  of  chalk  mixture  to 
make  the  total  measure  three  ounces,  mix  them  together  (accord- 
ing to  the  art- of  pharmacy),  and  on  the  label  write,  "Two  tea- 
spoonfuls  with  a  little  water  every  three  hours." 

According  to  custom,  a  prescription  is  written  in  six  sections, 
viz.: 

1.  The  name  of  the  patient  and  the  date.  (The  name  is 
omitted  from  a  prescription  for  venereal  disease,  or  where  it  is 


LIQUID    PRESCRIPTIONS  537 

best  for  esthetic  reasons,  as  in  prescribing  a  vaginal  douche.) 
The  pharmacist  is  expected  to  put  the  name  of  the  patient  on 
the  label,  but  unfortunately  does  not  always  do  so.  It  is  im- 
portant if  there  is  more  than  one  patient  in  the  family.  The 
name  is  also  a  check  on  the  pharmacist,  in  case  he  should  send 
the  wrong  bottle,  etc. 

2.  The  symbol  fy  (pronounced  R  X,  but  always  written  as  a 
capital  R  with  the  tail  crossed).  This  is  placed  at  the  upper 
left-hand  corner  preceding  the  names  of  the  ingredients.  It  is 
used  at  present  as  an  abbreviation  of  the  Latin  word  "Recipe," 
the  imperative  of  the  verb  recipio,  I  take.  It  means,  therefore, 
"Take  thou,"  and  is  always  followed  by  the  accusative  case. 

3.  The  name  and  quantity  of  each  ingredient.  The  quantity 
may  be  a  weight,  a  measure,  or  a  number. 

4.  Directions  for  compounding— -whether  the  pharmacist 
shall  simply  mix  the  ingredients  (M.  or  Misce),  or  make  them 
into  an  emulsion,  or  into  pills,  or  capsules,  or  a  plaster,  etc. 

5.  Directions  for  the  label— -to  be  placed  there  by  the  phar- 
macist. These  are  always  preceded  by  the  term  S.  or  Sig., 
which  is  an  abbreviation  of  the  Latin  imperative  signa,  meaning 
write  or  label. 

6.  The  physician's  signature. 

LIQUID  PRESCRIPTIONS 

Liquid  medicines  for  internal  use  are  administered  by  measure 
only,  hence  it  is  the  custom  to  make  the  total  quantity  of  the 
prescription  such  that  its  dose  will  be  a  teaspoonful,  a  dessert- 
spoonful, or  a  tablespoonful,  regardless  of  the  amount  of  active 
ingredients  present.  The  difference  between  the  measure  of  the 
active  ingredients  and  the  measure  of  the  dose  is  made  up  by 
the  vehicle.  It  is  for  this  reason  that  in  this  country  we  measure 
liquids  instead  of  weighing  them,  and  vary  the  amount  of  the 
vehicle  or  diluent  as  needed  to  make  the  total  the  number  of 
readily  measured  doses  desired.  Thus  of  the  vehicle  we  employ 
"q.  s.  ad  §iv,"  i.  e.,  as  much  as  may  be  needed  for  four  ounces 
(or  whatever  total  quantity  is  desired),  regardless  of  the  amount 
of  active  ingredients  present. 

The  necessity  for  this  may  be  illustrated  by  the_  following 
prescription.  If  we  wish  to  give  10  minims  of  the  tincture  of 
nux  vomica  at  each  dose  in  the  following  bitter  appetizer  and 
tonic  mixture: 

1^      Tinct.  nucis  vomicae oss 

Tinct.  cardamomi  comp q.  s.  ad  5u] 

M.  et  Sig. — One  dram  in  water  t.  i.  d.  a.  c. 


538  PHARMACOLOGY  AND   THERAPEUTICS 

This  calls  for  24  doses,  containing  240  minims  of  the  tincture 
of  nux  vomica,  i.  e.,  each  dose  contains  10  minims.  If  this 
should  be  written: 

1$      Tinct.  nucis  vomicae 3  ss 

Tinct.  cardamomi  comp oiij 

the  total  quantity  of  the  prescription  would  be  5  hiss,  or  28  doses, 
and  each  dose  of  the  tincture  of  nux  would  be  8f  minims. 
Another  reason  for  avoiding  this  type  of  prescription  is  that  the 
quantities  make  an  irregular  total,  and  do  not  fit  any  standard 
sized  bottle. 

Measures. — The  measures  used  by  patients  are:  drop, 
teaspoon,  dessertspoon,  tablespoon,  sherry  glass,  wineglass, 
tea-cup,  and  glass  or  tumbler. 

Drops. — Drops  are  uncertain  measures,  their  size  differing 
according  to  the  viscosity  of  the  liquid,  the  temperature,  the 
fulness  of  the  container,  the  surface  from  which  dropped,  the 
rapidity  of  dropping,  etc.  Drop  bottles  and  medicine-droppers 
or  pipets  may  be  had,  but  these  vary  greatly  in  the  size  of  their 
orifices,  and  consequently  in  the  size  of  their  drops.  For  ex- 
ample, with  five  medicine-droppers  bought  at  different  drug- 
stores by  the  writer,  60  minims  of  the  tincture  of  nux  vomica 
required  respectively  200, 172, 167, 142,  and  132  drops,  while  from 
the  shop  bottle  containing  the  tincture  it  took  125  drops.  Of 
commercial  droppers,  the  only  one  that  we  know  that  is  made 
with  a  standard  orifice  is  the  Barnes  Medicine  Dropper  (not  the 
Barnes  Eye  Dropper).  With  this  dropper  60  drops  of  water 
measure  60  minims;  of  other  liquids  the  number  of  drops  varies 
according  to  their  nature.  The  drop  is,  therefore,  not  a  certain 
measure.  We  have  several  times  prescribed  the  Barnes  Medi- 
cine Dropper  and  found  that  the  druggist  sent  instead  a  dropper 
with  a  much  smaller  orifice. 

Approximately,  when  dropped  from  the  mouth  of  a  bottle, 
aqueous  liquids,  glycerin,  and  the  fixed  oils  measure  one  drop  to 
the  minim,  volatile  oils  and  strongly  alcoholic  liquids  2  drops  to 
the  minim,  ether  3  or  4  drops,  chloroform  5  drops,  and  bromoform 
6  drops. 

The  term  minim  should  not  be  used  in  the  directions  for  the 
patient  unless  the  patient  or  nurse  has  a  minim  glass  for  accurate 
measuring. 

Spoonfuls. — A  medicinal  teaspoonful  is  1  dram,  a  dessertspoon- 
ful is  2  drams,  a  tablespoonful  is  4  drams;  but,  unfortunately,  the 
spoons  in  common  use  are  not  made  to  standard,  and  hold  from 
25  to  50  per  cent,  more  than  these  amounts.  Hence  if  accuracy 
is  important,  it  is  a  good  plan  to  advise  the  use  of  measuring- 


VEHICLES   AND    FLAVORS  539 

glasses,  which  may  be  had  at  trifling  cost  correctly  graduated  on 
the  scale  of  one  dram  to  one  teaspoonful.  In  lieu  of  the  measur- 
ing-glass, DeLorme  suggests  that  we  reckon  on  six  teaspoonfuls 
to  an  ounce;  and  he  shows  how  much  such  a  procedure  tends  to 
simplify  the  calculation  of  quantities  in  prescriptions.  (See 
below.) 

Glassfuls. — A  sherry  glass  holds  about  2  ounces,  a  wineglass 
about  3  ounces,  a  glass  or  tumbler  about  8  ounces.  A  tea-cup 
holds  5  or  6  ounces. 

ADMINISTRATION  OF  LIQUIDS 

Vehicles  and  Flavors 

The  vehicle  is  the  diluent  or  solvent.  It  is  generally  em- 
ployed in  sufficient  quantity  to  make  the  dose  a  readily  measur- 
able amount.  A  vehicle  maybe — (a)  non-medicinal,  as  plain  water, 
or  a  flavored  liquid,  or  a  mucilaginous  liquid  to  hold  heavy  pow- 
ders in  suspension;  or  (b)  it  may  have  medicinal  value.  It  is  to 
be  remembered  that  a  prescription  is  often  rendered  more  palat- 
able and  no  less  efficient  through  the  medium  of  a  pleasant  tast- 
ing vehicle  or  an  added  flavor.  The  simple  vehicles  in  common 
use  are:  water,  the  flavored  waters  (anise,  cinnamon,  pepper- 
mint, wintergreen,  etc.),  alcohol,  sherry  wine,  aromatic  elixir, 
elixir  adjuvans  (incompatible  with  acids),  and  the  flavored 
syrups  (citric  acid,  almond,  ginger,  wild  cherry,  orange-peel, 
orange-flowers,  raspberry,  rose,  tolu,  and  the  compound  syrup 
of  sarsaparilla  which  contains  sarsaparilla,  licorice,  senna,  sassa- 
fras, anise,  and  wintergreen). 

Flavors. — Small  amounts  of  special  flavoring  substances,  with 
or  without  medicinal  properties,  are  frequently  added  to  prescrip- 
tions, especially  where  the  vehicle  is  plain  water  or  alcohol.  Such 
are:  (a)  Sweetening  agents,  as  sugar,  glycerin,  and  the  various 
syrups.  In  diabetes,  saccharin,  which  dissolves  in  alkaline  media, 
may  be  employed. 

(b)  Aromatics — the  waters  and  spirits  (bitter  almond,  anise, 
compound  spirit  of  orange,  cinnamon,  lavender,  peppermint, 
spearmint,  and  wintergreen),  the  elixirs,  the  fluidextract  of 
licorice  (incompatible  with  acids),  the  aromatic  fluidextract 
(made  of  cardamom,  ginger,  cinnamon,  and  nutmeg),  the  tinc- 
tures of  cardamom,  cinnamon,  ginger,  lemon-peel,  bitter  orange, 
sweet  orange,  tolu,  vanilla,  the  compound  tincture  of  cardamom 
(made  of  cardamom,  cinnamon,  and  caraway),  and  the  compound 
tincture  of  lavender  (made  of  lavender,  rosemary,  cloves,  cin- 
namon, and  nutmeg).  Many  of  the  flavored  syrups  combine 
sweetening  and  aromatic  properties. 


54-0  PHARMACOLOGY  AND   THERAPEUTICS 

Bitter  or  unpleasant  tastes  in  liquids  may  be  overcome  or 
partly  so  by  these  flavoring  substances  or  by  flavored  vehicles. 
Bitterness  may  be  especially  overcome  by  the  syrup  of  yerba 
santa.  (See  Part  II.)  Bitter  or  disagreeable  solids  are  sometimes 
made  up  into  flavored  liquid  mixtures. 

Colors  are  sometimes  added  to  watery-looking  liquids  for 
their  psychic  effect.  The  preparation  seems  more  like  "real 
medicine,"  and  if  it  is  a  powerful  remedy,  is  less  likely  to  be 
mistaken  for  something  harmless.  Colored  aromatic  tinctures, 
like  the  compound  tincture  of  lavender,  may  be  employed,  or 
tincture  of  persio,  or  carmine  (in  aqueous  liquid). 

(For  definitions  of  the  classes  of  liquids  employed,  see  Part  I.) 

ADMINISTRATION  OF  SOLIDS 

The  regular  diluent  for  powdered  drugs  dispensed  in  very 
small  quantities  is  sugar  of  milk.  Of  drugs  in  tablet  form,  the 
tablet  triturates  are  made  with  sugar  of  milk,  hypodermatic 
tablets  with  cane-sugar,  and  compressed  tablets  without  any 
diluent  except  in  a  few  cases  where  it  is  necessary  to  increase 
the  cohesive  properties  of  the  powder. 

For  pills,  the  ingredients  must  be  worked  together  into  a 
mass,  which  is  then  divided  equally  into  the  requisite  number  of 
parts.  These  parts  are  then  given  a  round  or  elliptic  shape. 
The  pills  must  be  plastic,  to  permit  their  shaping,  but  they  must 
be  firm  enough  to  retain  their  shape  on  standing. 

An  excipient  is  a  substance  employed  to  give  proper  con- 
sistence to  a  mass.  It  may  be  water,  glycerin,  glucose,  syrup, 
glycerite  of  starch,  extract  of  gentian,  etc.  The  choice  of  excipi- 
ent should  be  left  to  the  pharmacist.  For  oxidizable  substances, 
as  silver  nitrate  or  potassium  permanganate,  the  diluent  should 
be  an  inert  powder,  such  as  kaolin,  and  the  excipient  an  inert 
substance,  like  petrolatum. 

Pills  may  be  rolled  in  some  powder,  such  as  starch  or  lyco- 
podium,  to  prevent  their  sticking  together,  or  they  may  have 
a  special  coating.  The  more  common  coatings  are  gelatin,  sugar, 
and  silver.  Pills  intended  to  pass  through  the  stomach  un- 
changed, but  to  disintegrate  in  the  intestine,  are  known  as 
"enteric"  pills,  and  are  usually  coated  with  salol  or  keratin. 
These  coatings  are  insoluble  in  the  acid  gastric  juice,  but  dis- 
solve in  the  alkaline  intestinal  contents.  The  so-called  chocolate- 
coated  pills  are  really  only  gelatin  or  sugar-coated  pills  with 
chocolate  color.  The  objects  in  coating  pills  are:  to  improve 
their  appearance,  to  improve  their  keeping  qualities,  to  hide 
their  taste,  or  to  make  them  "enteric." 

To  hide  a  bitter  or  unpleasant  taste,  powders  may  be  dis- 


LATIN  541 

pensed  in  liquid  form  with  syrup  or  other  flavoring  material,  or 
may  be  made  into  capsules,  cachets,  or  coated  pills.  Drugs  of 
sticky  consistence,  such  as  extracts,  may  be  made  into  a  mass, 
divided  into  the  requisite  number  of  parts,  and  then  put  into 
capsules. 

Tablet  triturates  have  sugar  of  milk  as  a  basis,  and  their 
solubility  or  power  of  disintegration  depends  on  that  of  the  sugar 
of  milk.  They  can,  therefore,  be  swallowed  whole  without  fear 
of  non-disintegration.  They  are  best  suited  for  those  metallic 
and  alkaloidal  salts  of  which  the  dose  is  very  small.  Extracts 
and  other  vegetable  materials  should  be  used  in  tablet  triturates 
only  in  very  minute  quantity.  Tablet  triturates  for  diabetics 
may  be  made  with  some  non-carbohydrate.  Hypodermic  tablets 
are  usually  made  with  cane-sugar  to  insure  ready  solubility, 
but  they  readily  become  broken  on  handling. 

Compressed  tablets  vary  in  hardness  according  to  the  degree 
of  compression  to  which  they  have  been  subjected,  and  in  solu- 
bility according  to  the  nature  of  the  drugs  of  which  they  are 
made.  Compressed  tablets  of  readily  soluble  substances,  as 
ammonium  chloride  or  potassium  iodide,  should  be  dissolved 
in  water  before  taking,  or  taken  with  a  copious  draft  of  water. 
If  made  of  substances  that  are  insoluble  or  soluble  with  difficulty, 
as  bismuth  subnitrate  or  phenacetin,  they  should  be  broken  up 
before  swallowing. 

(For  other  solids  see  Definitions,  Part  I.) 

LATIN 

The  names  of  the  ingredients  are  always  written  in  Latin, 
for  the  following  reasons: 

1.  Latin  is  a  universal  language,  so  is  readable  anywhere. 

2.  It  is  a  dead  language,  so  is  not  subject  to  change. 

3.  77  is  the  language  of  science,  so  is  explicit,  and  is  not  am- 
biguous. In  the  names  of  plant-drugs,  for  example,  Aristolochia 
serpentaria  always  stands  for  the  same  plant  wherever  it  is 
grown,  while  its  English  synonym,  snakeroot,  is  applied  to 
different  plants  in  different  localities. 

4.  It  may  be  advisable  to  keep  from  the  patient  the  nature  of 
the  drug.  Patients  have  many  preconceptions  and  prejudices 
regarding  drugs.  One  patient  assures  the  doctor  that  he  is 
always  made  ill  by  calomel  or  phenacetin,  yet  obtains  great 
benefit  from  a  prescription  for  hydrargyri  chloridum  mite  or 
acetphenetidin.  Another  has  found  cascara  absolutely  useless 
for  his  constipation,  but  secures  a  comfortable  laxative  movement 
from  rhamnus  purshiana. 

Though    prescriptions    are    written    in    Latin,    prescription 


542  PHARMACOLOGY  AND   THERAPEUTICS 

writing  may  be  accomplished  with  very  little  knowledge  of  the 
language ;  for  the  construction  follows  rules  that  are  not  always 
those  of  classic  Latin;  and  the  customary  methods  of  abbrevia- 
tion enable  one,  without  fear  of  criticism,  to  omit  a  Latin  ending 
if  the  correct  one  is  not  known.  Approved  prescription  writing, 
however,  requires  some  knowledge  of  Latin  and  a  familiarity  with 
certain  rules.  The  following  information  about 'Latin  words 
is  not  given  with  any  intent  to  teach  that  language,  but  solely 
with  the  desire  to  facilitate  prescription  writing  for  those  who 
do  not  know  Latin. 


NOUNS 

A  general  rule  for  case-endings  in  the  name  of  ingredients 
is:  The  name  of  the  substance  or  the  class  of  remedy  takes  the 
genitive  ending  when  the  quantity  is  a  weight  or  measure;  and  the 
accusative  ending  when  the  quantity  is  a  number. 

The  genitive  case  is  the  possessive,  implying  the  preposition 
"of."  For  example,  1$  Syrupi  scillae  compositi,  5ij,  may  be 
translated  literally  "Take  (thou)  2  ounces  of  the  compound 
syrup  of  squill."  1^  Acetanilidi,  gr.  xxx,  is  "Take  30  grains  of 
acetanilid. "  The  object  of  the  verb  "recipe"  in  these  cases  is 
the  word  for  ounces  (uncias)  or  grains  (grana),  the  plural  accusa- 
tive. 

The  accusative  case  represents  the  object  of  a  verb.  When  the 
quantity  is  a  number,  this  number  is  a  numeral  adjective;  and 
the  object  of  the  verb  recipe  is  the  name  of  the  numbered  objects. 
For  example:  1$  Capsulas  acetphenetidini,  aa  gr.  v,  No.  xij — 
"Take  12  capsules  of  phenacetin,  each  of  5  grains."  That  is, 
"Capsulas"  is  the  object  of  the  verb  recipe.  The  term  No. 
(numero)  is  customarily  placed  before  numbers  of  this  kind. 
It  may  be  translated  ''in  number."  Thus  the  prescription 
might  be  read:  "Take  capsules  of  phenacetin,  each  of  5  grains, 
and  in  number,  12."  The  genitive  singular  ending  is  the  one 
most  required,  and  this,  with  the  accusative  singular  and  plural, 
are  all  that  need  be  learned.  The  case-endings  of  nouns  used  in 
prescriptions  are: 

Gen. 

1.  Of  nouns  ending  in  a  (fem.),  as  quinina.  ...       ae 

2.  Of  nouns  ending  in  us  (masc),  as  strophan- 

tus        i 

3.  Of  nouns  ending  in  um  (neuter),  as  chlo- 

ralum j 

4.  Almost  all  other  nouns is 


Singular 

Ace. 

Plural 
Ace. 

am 

as 

um 

OS 

um 
em 

a 
es^masc.) 
es  (fem.) 
a  (neuter) 

ADJECTIVES 


543 


Of  this  last  class,  most,  but  not  all,  have  a  connecting  link, 
d,  t,  r,  etc.,  between  the  root  of  the  word  and  the  ending. 

Examples  giving  the  nominative  and  genitive  endings  are: 
With  the  nominative  ending: 


In  is:     Cannabis,  cannabis.  In  o: 

Digitalis,  digitalis. 

Hamamelis,  hamamelidis. 

Pulvis,  pulveris. 

Arsenis,  arsenitis.  In  r: 

In  as:    Nitras,  nitratis. 

Sulphas,  sulphatis. 

Asclepias,  asclepiadis.  In  s: 

Mas,  maris. 
In  ma:  Magma,  magmatis. 

Theobroma,  theobromatis. 

Physostigma,  physostigmatis.  In  x: 

In  c:      Lac,  lactis. 
In  I:      iEthyl,  aethylis. 

Alcohol,  alcoholis. 

Mel,  mellis. 
In  n:     Limon,  limonis. 

Semen,  seminis. 

Erigeron,  erigerontis. 


Solutio,  solutionis. 
Mucilago,  mucilaginis. 
Pepo,  peponis. 
Sapo,  saponis. 
Liquor,  liquoris. 
/Ether,  aetheris. 
Zingiber,  zingiberis. 
Adeps,  adipis. 
Pars,  partis. 
Flos,  floris. 
Juglans,  juglandis. 
Borax,  boracis. 
Rumex,  rumicis. 
Filix,  filicis. 
Calx,  calcis. 
Nux,  nucis. 


Exceptions  to  Rule  i  are  those  ending  in  ma,  as,  theobroma, 
theobromatis;  physostigma,  physostigmatis. 

Exceptions  to  Rule  2  are  five  in  number,  as  follows:  Rhus, 
rhois;  cornus,  cornus;  fructus,  fructus;  quercus,  quercus;  spiritus, 
spiritus. 

Of  aloe  (fern.)  the  genitive  is  aloes,  the  accusative,  aloen. 
Of  eriodictyon  the  genitive  is  eriodictyi;  of  toxicodendron, 
toxicodendri.  Dies  and  res  are  employed  in  the  ablative  case 
only,  as:  ter  in  die;  pro  re  nata. 

Indeclinable  nouns,  i.  e.,  those  having  the  same  ending  in  all 
cases,  are:  jaborandi,  sassafras,  and  azedarach,  and  most  nouns 
ending  in  u,  and  some  in  0,  as  buchu,  catechu,  condurango, 
cusso,  kino,  matico.  Some  which  are  declinable,  but  which 
have  no  change  in  the  genitive,  are :  berberis,  cannabis,  digitalis, 
hydrastis,  sinapis;  cornus,  fructus,  quercus,  spiritus. 

ADJECTIVES 

Adjectives  agree  in  number,  gender,  and  case  with  the  noun 
which  they  modify,  (a)  Those  ending  in  us  (masculine),  a 
(feminine),  um  (neuter),  are  of  the  second  declension,  and  take 
the  same  case-endings  as  nouns  with  the  same  terminals,  as  in 
Rules  1,  2,  and  3.  The  most  employed  are:  albus  (white), 
amarus  (bitter),  aromaticus  (aromatic),  benzoinatus  (benzoin- 
ated),  camphoratus  (camphorated),  catharticus  (cathartic), 
colatus    (strained),    compositus    (compound),    corrosivus    (cor- 


544  PHARMACOLOGY   AND   THERAPEUTICS 

rosive),  dilutus  (diluted),  durus  (hard),  exsiccatus  (dried), 
flavus  (yellow),  fluidus  (fluid),  frigidus  (cold),  granulatus  (granu- 
lated), hydra tus  (hydrated),  inspissatus  (inspissated),  magnus 
(great),  niger  (black),  parvus  (small),  ponderosus  (heavy), 
prsecipitatus  (precipitated),  praeparatus  (prepared),  purificatus 
(purified),  rectificatus  (rectified),  reductus  (reduced),  rubrus 
(red),  saturatus  (saturated),  tepidus  (warm),  unus  (one).  Duo 
(two)  has  accusative  duos. 

Examples  of  agreement  with  the  noun  are:  syrupus  aromati- 
cus,  fluidextractum  aromaticum,  cochlearia  parva,  pilulas  cathar- 
ticas,  tinctura  lavandulae  composita,  pulveris  glycyrrhizae  com- 
positi. 

(b)  Those  ending  in  is  (masculine  and  feminine),  e  (neuter), 
take  endings  as  follows: 

is  takes  gen.  is,  ace.  em,  ace.  plural  es. 

e  takes  gen.  is,  ace.  e,  ace.  plural  ia. 

Examples  are:  sequalis  (equal),  animalis  (animal),  dulcis 
(sweet),  fortis  (strong),  glacialis  (glacial),  levis  (light),  mitis 
(mild),  mollis  (soft),  omnis  (every),  simplex,  icis  (simple), 
solubilis  (soluble),  talis  (such),  tres  (three),  vegetabilis  (vege- 
table), viridis  (green).  Some  ending  in  ens  have  genitive  entis, 
and  ace.  entem  or  ente,  as  adstringens  (astringent),  bulliens 
(boiling) ,  eff ervescens  (effervescing) ,  f ervens  (hot) ,  recens  (fresh) . 

Examples  of  agreement  with  the  noun  are:  succi  limonis 
recentis,  partes  aequales,  amygdala;  dulcis,  hydrargyri  chloridum 
mite,  doses  tales. 

Adjectives  of  one  declension  may  modify  nouns  of  another 
declension,  but  each  takes  the  ending  of  its  own  declension. 

OTHER  WORDS 

Besides  nouns  and  adjectives,  there  are  employed  in  the 
directions  for  the  pharmacist  and  for  the  label  a  few  special 
words  that  should  be  known.    They  are: 

i.  Verbs — adde  (add),  bulliat,  bulliant  (let  it  or  them  boil), 
cola  (strain),  coletur  (let  it  be  strained),  detur,  dentur  (let  it  or 
them  be  given),  divide  (divide),  extende  supra  (spread  upon), 
fiat,  fiant  (let  it  be,  let  them  be),  filtra  (filter),  misce  (mix), 
mitte  (send),  pone  (place),  signa  (write),  solve  (dissolve),  tere 
(rub  in  a  mortar;  triturate). 

2.  Adverbs — bene  (well),  statim  (immediately;  at  once). 

3.  Prepositions — (a)  ad  (for;  up  to),  ante  (before),  in  (into), 
supra  (upon),  post  (after) ,  govern  the  accusative.  After  a  transi- 
tive verb  in  governs  the  accusative  and  expresses  the  English 
into,  as  ''divide  in  capsulas"  (divide  into  capsules).     After  an 


THE   FORM   OF   A   PRESCRIPTION  545 

intransitive  verb,  in  takes  the  ablative,  and  is  equivalent   to 
the  English  in,  as  "in  aqua"  (in  water). 

(b)  cum  (with),  pro  (for;  according  to),  sine  (without),  in 
(in),  govern  the  ablative. 

(c)  Ana  (each  of;  of  each)  governs  the  genitive. 
4.  Conjunctions — aut  (or),  et  (and),  vel  (or). 


THE   FORM    OF  A   PRESCRIPTION 

Almost  all  prescriptions  are  of  two  classes,  viz.:  I.  Material 
to  be  sent  in  bulk,  as  liquids,  ointments,  mixtures  of  powders, 
etc.  II.  Objects  to  be  counted,  as  pills,  tablets,  powders,  etc. 
Hence,  it  is  easy  to  learn  one  or  two  forms  of  each  of  these 
classes.  Prescriptions  are  spoken  of  as  simple  when  they  con- 
tain but  one  preparation,  and  compound  when  they  include  more 
than  one.  The  following  types  represent  variations  in  the  two 
classes : 

1.  Material  Dispensed  in  Bulk. — /.  Simple   Prescriptions.— 

1$     Linimenti  chloroformi 5  ij 

Sig. — Rub  well  over  shoulder  every  four  hours. 

1$     Pulveris  glycyrrhizse  compositi 5j 

Sig. — Take  a  level  teaspoonful  in  water  each  night. 

1$     Unguenti  hydrargyri  oxidi  flavi 5ss 

Sig. — Rub  into  eyelids  morning  and  night. 

2.  Compound  Prescriptions. — (a)  Where  special  directions 
to  the  pharmacist  would  be  superfluous,  i.  e.,  where  no  possible 
method  of  mixing  according  to  the  pharmacist's  art  could  make 
anything  other  than  that  desired.  In  such  a  case  the  directions 
for  compounding  are  limited  to  M.  or  Misce,  and  it  is  a  super- 
fluity to  write  M.  et  ft.  mistura,  M.  et  ft.  unguentum,  M.  et 
ft.  collyrium  (eye-wash),  etc.    Examples  are: 

1^      Sodii  bicarbonatis o  j 

Fluidextracti  rhamni  purshianas oij 

Misturas  rhei  et  sodse q.  s.  ad  §  "j 

M.  et  Sig. —  oij  in  water  t.  i.  d.  2  h.  p.  c. 

1$     Sulphuris  prascipitati oij 

Olei  cadini oiss 

Unguenti  zinci  oxidi q.  s.  ad  5j 

M.  Sig. — Apply  to  itching  area  twice  a  day. 
1$     Magnesii  oxidi oij 

Sodii  chloridi 5  j 

Sodii  bicarbonatis 3  ss 

M.   et  Sig. — One  level  teaspoon  in  half  a  glass  of  hot  water  half  an  hour 

before  breakfast. 

(b)  Where  special  directions  to  the  pharmacist  are  necessary 
or  serve  to  avoid  uncertainty.  Such  a  necessity  is  only  occasional. 

35 


546  PHARMACOLOGY   AND   THERAPEUTICS 

1$      Buchu oiv 

Matico 5  ij 

Aquas q.  s.  ad  5  viij 

Ft.  infusum. 

Sig. —  oij  in  a  wineglass  of  water  every  four  hours. 

In  special  cases  directions  for  compounding  may  be  placed 
after  a  portion  of  the  ingredients,  as: 

T$     Peponis oij 

Granati, 

Cusso aa.  3  j 

Aquae  bullientis q.  s.  ad  §  j 

Ft.  infusum,  cola  et  adde — 

Oleoresinae  aspidii 3  j 

Mucilaginis  acaciae §  ss 

Aquae q.  s.  ad  5  viij 

Sig. — Take  half  statim  and  half  in  three  hours. 

II.    Objects  to  be  Counted. — i.  Commonly  Kept  Ready-made — 

(a)  With  standard  name,  or  with  only  one  ingredient: 

Tj     Pilulas  catharticas  compositas No.  iij 

Sig. — Take  at  bedtime. 

B;    Capsulas  quininae  sulphatis,  gr.  v No.  xij 

Sig. — One  t.  i.  d.  p.  c. 

(b)  With  no  standard  name — 

1$     Olei  ricini njiiss 

Salolis gr.  iiss 

M.  et  ft.  capsula  No.  j.  Mitte  tales  No.  xx. 
Sig. — One  q.  4  h. 

(This  omission  of  multiplication  should  never  be  resorted  to 
except  for  ready-made  objects.   Itwould  suggest  a  lazy  physician.) 
2.  To  Be  Made  Up  Extemporaneously — 

B;     Acetanilidi gr.  xxx 

Ft.  chartae  No.  vj. 

Sig. — One  q.  3  h. 

Tfy     Strychninae  sulphatis gr.  *4 

Acetphenetidini .gr.  xxiv 

Acetanilidi gr.  xvj 

M.  et  ft.  capsulae  No.  viij.     (Or  M.  et  ft.  in  capsulas  No.  viij.) 
1$     Aloes  purificatE gr.  xviij 

Massae  hydrargyri 3  ss 

Olei  menthae  piperitae gtt.  iij 

M.  et  ft.  pilulae  No.  xij.     (Or  M.  et  ft.  in  pilulas  No.  xij.) 
Sig. — Two  at  bedtime  once  a  week. 


The  first  example  of  this  section  may  also  be  written — 

B;     Chartas  acetanilidi  gr.  v  (or  "  aa  gr.  v  ") .  .  No.  vj. 
Sig. — One  q.  3  h. 

The  accusative  plural  forms  of  the  names  of  objects  to  be 


FIGURING   THE   QUANTITIES  547 

counted  are:  cache tas  (cachets),  capsulas  (capsules),  chartas 
or  chartulas  (powders),  pilulas  (pills),  suppositoria  (supposi- 
tories), tabellas  (tablets),  tabellas  trituratas  (tablet  triturates), 
tabellas  hypodermaticas  (hypodermic  tablets),  trochiscos  (tro- 
chees) . 

If  it  is  desired  that  the  pharmacist  send  a  piece  of  apparatus 
for  the  administration  of  the  remedy,  such  as  a  camel's-hair 
pencil,  a  throat  brush,  an  eye-dropper,  a  medicine-dropper,  an 
eye-cup,  this  may  be  indicated  by  writing  the  name  on  the  lower 
left-hand  corner  of  the  prescription  blank.    Thus: 

1$     Sol.  sat.  acidi  borici 3  j 

Sig. — Warm  and  use  in  eye-cup  every  three  hours. 

W.  M.  Johnson. 
One  eye-cup. 

FIGURING  THE  QUANTITIES 

To  acquire  careful  habits  it  is  wise,  in  writing  a  compound 
prescription,  to  put  down  the  names  of  all  the  ingredients  desired 
before  inserting  the  quantities.  Then  multiply  the  number  of 
doses  by  the  desired  dose,  and  set  down  the  result  opposite  the 
name  of  the  ingredient.  Total  quantities  are  usually  expressed 
in  the  nearest  half  or  whole  number  rather  than  in  fractional 
amounts,  the  error  in  such  a  case  being  small  in  proportion  to 
the  whole  amount  of  the  dose. 

In  a  liquid  prescription  the  name  of  the  vehicle  always  comes 
last,  followed  by  q.  s.  ad  and  the  total  quantity  of  the  prescrip- 
tion. 

A  number  of  ways  to  promote  ease  in  the  calculations  have 
been  suggested.  A  one-ounce  mixture  may  be  reckoned  as  eight 
teaspoonful  doses,  a  two-ounce  as  15  teaspoonfuls,  a  three-ounce 
as  24  teaspoonfuls,  and  a  four-ounce  as  30  teaspoonfuls. 

Hence  a  two-ounce  bottle  contains  15  or  16  teaspoonfuls;  a 
four-ounce  bottle  contains  15  or  16  dessertspoonfuls;  an  eight- 
ounce  bottle  contains  15  or  16  tablespoonfuls. 

One  simple  rule  is:  For  an  eight-ounce  mixture  with  tea- 
spoonful  dose  prescribe  as  many  drams  of  the  ingredient  as 
you  desire  minims  or  grains  at  a  dose;  for  a  four-ounce  mixture, 
half  as  many  drams;  for  a  three-ounce  mixture,  two-fifths  as 
many,  and  for  a  two-ounce  mixture,  one-fourth  as  many.  In 
other  words,  in  a  two-ounce  mixture  with  teaspoonful  dose  one 
dram  of  the  substance  gives  a  4-grain  or  minim  dose ;  in  a  three- 
ounce  mixture  one  dram  gives  a  2^-grain  or  minim  dose;  in  a 
four-ounce  mixture  one  dram  gives  a  2-grain  or  minim  dose. 

Example :  The  single  dose  of  the  prescription  being — 


548  PHARMACOLOGY  AND   THERAPEUTICS 

1$     Ammonii  chloridi gr.  v 

Syrupi  ipecacuanha ngviij 

Aquae q.  s.  ad  5  j 

2-Ounce  Mixture  3-Ounce  Mixture    4-Ounce  Mixture 

\yi  drams gr.  lxxv  oij  oiiss 

2      drams oij  5iij  5iv 

to  2  ounces ad  5  ij  ad  5  iij  ad  5  iv 

Observe  that  increase  in  size  of  mixture  requires  increase 
in  amount  of  active  ingredients.  Increase  in  dose  of  mixture 
requires  decrease  in  amount  of  active  ingredients. 

Where  the  ordinary  spoons  are  to  be  used  and  not  a  measur- 
ing-glass, a  method  recommended  by  De  Lorme  is  to  assume 
six  teaspoonfuls  to  an  ounce  and  follow  this  rule:  "Employ  ^2 
dram  to  each  ounce  for  five-grain  or  five-minim  doses  in  each 
teaspoonful. "  This  does  not  apply  to  preparations  for  external 
use,  i.  e.,  those  not  measured  by  the  spoon. 

There  is  a  method  advocated  by  some,  of  figuring  out  the 
doses  in  the  English  system,  but  writing  the  prescription  accord- 
ing to  the  metric  system.  The  rule  is  to  write  always  for  sixteen 
doses,  i.  e.,  a  two-ounce  mixture  (written  60  c.c.)  if  the  dose  is  a 
teaspoonful,  a  four-ounce  mixture  (written  120  c.c.)  if  the  dose 
is  a  dessertspoonful,  an  eight-ounce  mixture  (written  240  c.c.) 
if  the  dose  is  a  tablespoonful.  Then  put  down  for  each  ingredient 
as  many  grams  or  cubic  centimeters  as  you  desire  grains  or 
minims  per  dose.  The  above  prescription  by  this  method  would 
read — 

1}     Ammonii  chloridi 5.0 

Syrupi  ipecacuanha? 8.0 

Aquae q.  s.  ad  60.0 

Sixteen  powders  or  pills  or  capsules  may  be  prescribed  in 
the  same  way;  eight  powders  would  require  half  as  many  grams 
as  grains  per  dose,  etc.  This  is  an  easy  method  for  older  doctors 
who  know  their  doses  in  the  English  system,  and  desire  to  make 
their  prescriptions  conform  with  the  metric  system.  But  as  it 
requires  thinking  of  doses  in  grains  and  minims,  and  yet  writing 
in  metric  amounts,  it  is  an  unwise  method  for  a  student  to  learn. 
If  he  is  going  to  write  metric  prescriptions,  he  had  better  learn 
his  doses  at  the  outset  in  the  metric  amounts. 

In  prescriptions  for  children  a  simple  application  of  the 
author's  age-weight  rule  for  dosage  (see  Part  I)  is  to  make  the 
prescription  for  two  ounces  with  teaspoonful  dose,  and  to  put 
down  for  each  ingredient  half  as  many  grains  or  minims  as  its 
adult  dose,  multiplied  by  the  age  of  the  patient  plus  3.  Thus,  for 
a  child  of  two  years  the  prescription  above  would  read: 


FIGURING   THE    QUANTITIES  549 

1^     Ammonii  chloridi gr.  xij 

Syrupi  ipecacuanhse njjxx 

Aquae q.  s.  ad  g  ij 

If  using  Cowling's  rule,  the  prescription  may  be  a  three-ounce 
mixture  with  teaspoonful  dose,  i.  e.,  24  doses.  Then  the  adult 
dose  multiplied  by  the  age  at  next  birthday  will  be  the  total 
amount.     For  a  child  of  two  it  would  read: 

1$     Ammonii  chloridi gr.  xv 

Syrupi  ipecacuanhas njjxxiv 

Aquae q.  s.  ad  5  iij 

For  12  doses  it  would  read  half  these  amounts. 

"Lazy  Man"  Prescriptions. — The  method  of  writing  bulk 
prescriptions,  by  putting  down  the  single  dose  of  each  ingredient 
and  directing  the  pharmacist  to  send  a  certain  number  of  such 
doses  (mitte  tales  doses),  is  known  as  the  "lazy  man's  method," 
and  is  not  approved.  Such  a  method  is  good  usage  only  in  pre- 
scriptions for  objects  of  standard  formula,  such  as  pills,  capsules, 
etc.,  which  are  understood  to  be  kept  ready  made  by  the  phar- 
macist.    (See  Types  of  Prescriptions.) 

A  shot-gun  prescription  is  one  that  contains  a  number  of 
substances  which  have  no  essential  therapeutic  affinity.  It  is 
the  result  of  an  ignorant  attempt  to  hit  the  trouble,  no  matter 
what  may  be  its  nature.  Warburg's  tincture  is  a  good  example 
of  such. 

Good  Usage. — In  prescription  writing,  clearness  is  the  im- 
portant thing  and  Latin  is  the  medium  of  expression,  but  cer- 
tain forms  have  become  approved,  and  certain  modes  of  expres- 
sion are  accepted  as  the  best  custom.  The  following  precepts 
are  according  to  "good  usage": 

1.  Each  ingredient  name  shall  have  a  separate  line. 

2.  Each  line  begins  with  a  capital  letter. 

3.  Ditto  marks  are  not  permissible. 

4.  The  names  of  the  most  active  ingredients  are  placed  first, 
the  names  of  flavors  and  correctives  afterward,  the  name  of  the 
diluent  last.  In  a  liquid  prescription  the  names  of  solids,  if  active 
medicinally,  before  those  of  liquids,  and  the  vehicle  last. 

5.  In  a  title  the  name  of  the  class  of  preparation  (as  pilula, 
tinctura,  elixir,  etc.)  comes  first;  a  modifying  adjective  usually 
last,  as  syrupi  sarsaparillae  compositi.  Of  salts,  the  name  of  the 
base  first,  as  sodii  bromidi;  of  acids,  the  term  for  acid  first,  as 
acidi  hydrochlorici. 

6.  Latin  is  regularly  employed  for  the  names  of  the  ingre- 
dients and  for  the  directions  for  compounding. 


550  PHARMACOLOGY  AND  THERAPEUTICS 

7.  In  the  directions  for  the  label,  Latin  is  employed  only  in 
certain  recognized  expressions,  hence  Latin  and  English  are 
mixed  indiscriminately.  The  pharmacist  writes  these  direc- 
tions on  the  label  in  English. 

8.  When  in  doubt  as  to  the  correct  Latin  expression,  write 
in  English;  when  uncertain  of  the  correct  Latin  ending,  omit  it. 
The  understanding  of  the  physician's  order  by  the  pharmacist 
is  of  more  importance  than  the  correctness  of  the  Latin.  Com- 
plicated Latin  constructions  add  the  risk  of  being  wrongly 
interpreted  by  the  pharmacist,  who  is  not  of  necessity  a  Latin 
scholar. 

9.  For  amounts  over  two  ounces  make  the  total  of  a  liquid 
prescription  conform  with  the  sizes  of  bottle  found  in  the  phar- 
macies; for  if  a  bottle  is  only  partly  filled,  the  patient  may  think 
that  some  of  the  medicine  has  been  spilled  or  an  error  made  by 
the  pharmacist.  The  vials  used  in  the  United  States  are:  1,2, 
and  4  dram,  1,  2,  3,  4,  6,  8,  12,  16,  and  32  ounce. 

10.  In  acute  illness  order  a  small  number  of  doses,  both  to 
permit  frequent  change  in  the  treatment  and  to  avoid  having 

.  the  medicine  outlast  the  sickness.  The  larger  amounts  may  be 
prescribed  if  the  dose  is  to  be  repeated  frequently,  or  if  the 
medicine  is  to  be  continued  definitely  without  change  for  a  long 
time. 

n.  When  writing  for  more  than  the  ordinary  dose  of  a 
potent  drug,  as  for  one  grain  of  morphine  sulphate  or  jo  grain 
of  strychnine  sulphate,  always  double  underline  the  quantity 
or  write  O.  K.  or  dose  correct,  otherwise  the  pharmacist  may  think 
it  an  error  and  refuse  to  dispense  the  prescription  till  the  doctor 
is  communicated  with.  Do  not  employ  exclamation  marks 
for  this  purpose,  for  these  have  been  mistaken  for  Roman  nume- 
rals. Professor  Remington  reports  a  prescription  for  one  grain 
of  morphine  sulphate  to  be  divided  into  two  powders.  The 
physician  intended  to  write  R  Morphinae  sulphatis,  gr.  j  ! ! — the 
exclamation  marks  indicating  that  he  intended  the  large  dose. 
But  he  did  actually  write  R^  Morphinse  sulphatis,  gr.  ;;;,  the 
exclamation  marks  being  turned  upside  down. 

12.  WThen  the  formula  or  name  of  the  medicine  is  desired 
on  the  label  the  term  "Label,"  "R;  on  label,"  "Formula  on 
label,"  may  replace  or  be  added  to  other  directions  for  the  label. 
Examples  are:  Sig. — Label,  or  Sig. — Take  three  times  a  day — 
Formula  on  label. 

13.  The  terms  "For  external  use"  and  "Shake  before  using" 
need  not  be  specified  in  the  directions,  for,  when  the  nature  of  the 
preparation  indicates  it,  these  are  regularly  placed  upon  the 
bottle  by  the  pharmacist.    But,  unless  the  physician  so  directs, 


ABBREVIATIONS  55 1 

the  term  "Poison!"  is  never  placed  upon  a  prescription  for 
internal  use,  as  for  strychnine  tablets  or  Fowler's  solution.  And 
it  is  often  omitted  from  poisonous  preparations  for  external  use, 
as  belladonna  liniment. 

14.  The  letters  P.  P.  following  a  patient's  name  stand  for 
"poor  patient,"  and  secure  from  the  pharmacist  his  lowest 
price.  The  expressions  "ne  repetatur, "  or  "not  to  be  repeated, " 
and  "give  no  copy,"  are  regularly  heeded  by  the  pharmacist. 

15.  The  use  of  the  term  "as  directed"  or  "use  as  directed" 
as  the  sole  direction  for  the  patient  should  be  avoided  if  possible, 
for  it  does  not  indicate  to  the  druggist  how  or  in  what  dose  the 
remedy  is  to  be  employed.  The  physician  thus  lacks  the  phar- 
macist's valuable  check  upon  the  prescription.  If  for  esthetic 
or  other  reasons  it  is  desired  to  omit  the  directions,  as  for  douches, 
injections,  etc.,  they  should  be  given  to  the  patient  in  writing; 
for  patients,  especially  those  who  are  nervous  or  quite  ill,  are 
prone  to  forget  verbal  directions,  or,  what  is  worse,  to  remember 
(!)  them  wrongly. 

16.  Where  there  can  be  no  possible  misinterpretation,  abbre- 
viation may  be  good  usage.     See  below. 

17.  Never  sign  a  prescription  or  let  it  get  out  of  your  hands 
without  first  reviewing  it.  Because  of  distraction  of  the  physi- 
cian's attention  by  anxious  or  talkative  friends,  or  for  other 
reasons,  errors  in  prescriptions  are  of  frequent  occurrence.  The 
most  common  error  is  omission  or  transposition  of  the 
amounts  of  the  ingredients.  For  example,  one  recently  seen 
by  the  writer  called  for  potassium  iodide,  gr.  j,  and  mercuric 
iodide,   5iij\  the  amounts  being  transposed. 

Note. — If  a  pharmacist  'phones  you  or  calls  upon  you  rela- 
tive to  the  interpretation  of  one  of  your  prescriptions,  do  not 
take  offense  as  if  it  were  an  insult  for  any  one  to  suppose  your 
handiwork  anything  less  than  perfect.  On  the  contrary,  be 
grateful  to  the  pharmacist;  for  he  will  protect  you  and  will  not 
tell  the  patient  of  your  error,  even  though  he  has  to  shoulder 
the  blame  himself  for  the  delay  in  the  dispensing  of  the  prescrip- 
tion. The  pharmacist  is  no  more  prone  than  other  people  to 
make  trouble  for  himself  unnecessarily,  and  if  he  questions  one 
of  your  prescriptions,  you  may  take  it  for  granted  that  he  has  a 
reason  for  his  action,  even  though  it  may  not  be  apparent  to  you. 

ABBREVIATIONS 

When  there  can  be  no  possible  mistake  in  meaning,  abbre- 
viations are  allowable  as  follows: 

I.  Of  Ingredients. — (a)  In  the  name  of  the  class  of  prepara- 
tions, as  elix.,  tinct.,  syr.,  pil.,  suppos.,  ungt.  (or  ung.).     The 


552  PHARMACOLOGY  AND  THERAPEUTICS 

abbreviation  Tr.  should  not  be  employed  for  tincture,  as  in 
script  form  it  has  frequently  been  incorrectly  read  Fe. — i.  e., 
fluidextract. 

(b)  In  modifying  adjectives,  as  ceq.  for  aequalis,  comp.  for 
compositus,  ppt.  for  praecipitatus,  recent,  for  recentis,  sat.  for 
saturatus. 

(c)  In  amounts — q.  s.  for  quantum  sufficiat  (as  much  as  may 
be  required),  aa  for  ana  (of  each),  and  the  regular  symbols  of 
weights  and  measures. 

(d)  In  prepositions — c  for  cum,  s  for  sine. 

II.  In  the  Directions  for  Compounding. — (a)  In  nouns  and 
adjectives,  as  each.,  chart.,  pil.,  suppos.,  tab.,  tab.  trit.,  tab. 
hyp.,  troch.,  scat,  (scatulam  =  a  box),  dos.  tal.  (doses  tales  = 
such  doses). 

To  express  the  kind  of  coating  for  pills  write  argent,  (argenti- 
ferus)  =  silver-coated,  sacchar.  (sacchariferus)  =  sugar-coated, 
and  gelat.  (gelatinif erus) ,  or  g.  c.  =  gelatin-coated,  after  the  term 
for  pill.  The  terms  "keratin-coated"  and  "salol-coated"  are 
best  written  in  English.  To  order  that  powders  should  be  put 
in  waxed  papers,  write  for  chart,  cerat.  (chartas  ceratas).  Such 
are  used  for  efflorescent  or  deliquescent  drugs,  and  for  the  latter 
especially  if  the  patient  is  to  be  at  the  seashore  or  aboard  ship. 

(b)  In  verbs — ft.  for  fiat  or  fiant  (let  it  or  them  be  made), 
div.  for  divide  (divide),  M.  for  misce  (mix),  S.  or  Sig.  for  Signa 
(label),  bull,  for  bulliat  or  bulliant  (let  it  or  them  boil). 

An  example  of  the  use  of  these  abbreviations  might  be:  Ft. 
pil.  argent.  No.  xij  (Fiant  pilula  argentifera,  numero  duodecim) 
=  let  twelve  silver-coated  pills  be  made. 

III.  In  the  Directions  for  the  Label. — (a)  Relating  to  quan- 
tity— gtt.  (drop),  oj  (one  teaspoonful),  5ij  (one  dessertspoonful), 
5iv  (one  tablespoonful),  cochl.  parv.,  coch.  mag.  (cochlearia 
parva,  magna  =  small  or  large  spoon).  The  term  cochlearia 
might  properly  be  abandoned. 

(b)  Relating  to  the  time  of  taking — h.  (hour),  min.  (minute); 
stat.  (statim  =  at  once);  a.  c.  (ante  cibum  =  before  eating), 
p.  c.  (post  cibum  =  after  eating);  q.  h.,  q.  2  h.,  q.  3  h.,  q.  4  h. 
(quaqua  hora  =  every  hour,  every  two  hours,  etc.);  o.  d.,  b.  i.  d., 
t.  i.  d.,  4  i.  d.  (omne  die,  bis  in  die,  ter  in  die  =  daily,  twice  a  day, 
three  times  a  day,  etc.) ;  o.  m.,  o.  n.  (omne  mane  =  each  morning, 
omne  nocte  =  each  night) ;  M.  et  N.  (mane  et  nocte  =  morning 
and  night;  also  written  "mane  nocteque, "  and  "a.  m.  et  p.  m. "); 
s.  o.  s.,  p.  r.  n.  (si  opus  sit  =  if  there  is  necessity;  pro  re  nata  = 
when  required).  In  some  circles  a  distinction  is  made,  s.  0.  s. 
referring  to  one  dose  only,  and  p.  r.  n.  to  any  number,  its  inter- 
pretation being,  "whenever  needed." 


PRACTICE   IN   BULK   PRESCRIPTIONS  553 

(c)  In  aq.  (in  aqua  =  in  water). 

An  example  of  the  use  of  such  directions  would  be : 

Sig. —  5j  in  aq.  t.i.  d.  10  min.  a.c.  =  a  teaspoonful  in  water 
three  times  a  day,  ten  minutes  before  meals. 

Though  it  would  certainly  be  the  safest  plan  to  write  directions 
for  the  label  in  full  English,  it  is  not  the  custom  to  do  so. 

IV.  Special  abbreviations,  usually  placed  at  the  top  of  the 
prescription  blanks,  are  P.P.  =  poor  patient,  and  ne  rep.  =  ne 
repetatur  (not  to  be  repeated). 

Observe  that  the  proper  abbreviation  for  drops  is  gtt.  and  not 
gtts.,  for  grains  is  gr.,  for  grams  is  gm.,  and  for  pill  or  pills  is 
pil.  not  pill. 

I.    PRACTICE  IN  BULK  PRESCRIPTIONS 

According  to  the  forementioned  rules,  write  out,  correctly 
using  approved  abbreviations,  the  following  prescriptions. 
Ascribe  each  prescription  to  some  person,  e.  g.,  For  John,  For 
Willie,  For  Mr.  William  Hawkes,  Jr.,  For  Mrs.  Brown,  etc., 
date  the  prescription,  and  sign  with  your  own  name. 

A.  Liquids. — i.  Three  ounces  of  rhubarb  and  soda  mixture. 
Directions :  Two  teaspoonf uls  in  a  wineglass  of  water  three  times 
a  day,  two  hours  after  eating. 

2.  Twenty-four  teaspoonful  doses,  each  dose  containing  5 
minims  of  fluidextract  of  cascara,  and  rhubarb  and  soda  mixture 
to  make  up  the  remainder.  Directions,  a  teaspoonful  in  a  wine- 
glass of  water  an  hour  before  luncheon  and  dinner  and  at  bed- 
time. 

3.  Twelve  dessertspoonful  doses,  each  containing  5  grains  of 
sodium  bicarbonate,  40  minims  of  milk  of  magnesia  (magma 
magnesias,  N.  F.),  and  rhubarb  and  soda  mixture  to  make  the 
total.  Direct  that  the  dose  is  to  be  taken  in  a  little  water  one 
hour  after  meals. 

4.  Six  ounces  of  infusion  of  digitalis,  fresh  made  (recens, 
recentis).  Dose,  one  teaspoonful  with  water  every  four  hours. 
Have  the  name  of  the  preparation  placed  upon  the  label. 

5.  Twelve  doses  of  infusion  of  digitalis,  each  containing  fifteen 
grains  of  potassium  acetate.  Directions,  a  tablespoonful  with 
water  after  each  meal. 

6.  Sixteen  two-dram  doses  of  the  elixir  of  the  phosphates  of 
iron,  quinine  and  strychnine,  a  dose  to  be  taken  in  water  three 
times  a  day  after  meals. 

7.  Half  an  ounce  of  the  tincture  of  nux  vomica.  Directions, 
10  drops  in  water  three  times  a  day,  fifteen  minutes  before  eating. 
With  this,  order  a  Barnes  medicine-dropper. 

8.  One  ounce  of  Fowler's  solution.     Directions:    Begin  with 


554  PHARMACOLOGY  AND   THERAPEUTICS 

three  drops  in  water  three  times  a  day  after  eating,  and  increase 
one  drop  per  dose  each  day  till  the  dose  is  ten  drops. 

9.  One  ounce  of  a  saturated  solution  of  potassium  iodide. 
Directions :  Fifteen  drops  in  a  wineglass  of  water  after  each  meal. 
(Solutio,  solutionis  (fern.)  means  a  solution  of  any  kind.  Liquor, 
liquor  is  (masc.)  is  the  official  title  of  an  aqueous  solution  of  non- 
volatile substances.) 

10.  Two  drams  each  of  tincture  of  ferric  chloride,  glycerin, 
and  water.  Place  in  wide-mouth  bottle  (pone  in  w.  m.  hot.). 
Direct  that  it  be  employed  to  swab  the  throat  every  three  hours, 
and  order  the  druggist  to  send  a  throat  brush  and  a  Seidlitz 
powder.  (The  English  name,  not  the  U.  S.  P.  Latin  name,  is 
regularly  employed  for  the  last  mentioned.) 

11.  Three  ounces  of  a  saturated  solution  of  boric  acid.  Di- 
rections :  Use  warm  in  eye-cup  three  times  a  day.  Order  an  eye- 
cup  sent  with  it. 

12.  Half  an  ounce  each  of  oil  of  turpentine  and  camphorated 
oil.  Directions:  Rub  throat  twice  a  day  and  cover  with  flannel. 
Send  a  mustard-leaf  also. 

13.  Twenty  grains  of  salicylic  acid  and  sufficient  flexible 
collodion  to  make  a  quarter  of  an  ounce.  Directions:  Paint  on 
the  corn  every  night. 

14.  Two  doses,  each  containing  15  grains  of  chloral  hydrate 
and  30  grains  of  sodium  bromide,  dissolved  in  cinnamon  water. 
Directions:  One  tablespoonful  with  water  at  once,  and  the  other 
tablespoonful  two  hours  later  if  needed. 

15.  Twenty- four  tablespoonful  doses  of  emulsion  of  cod-liver 
oil.     Direct  that  the  dose  be  taken  three  times  a  day  after  meals. 

16.  Take  half  an  ounce  of  buchu,  make  into  an  infusion  with 
five  ounces  of  boiling  water,  strain,  and  add  two  drams  of  potas- 
sium bicarbonate  and  sufficient  cinnamon  water  to  make  half  a 
pint.  Directions:  A  tablespoonful  every  four  hours.  (How 
much  potassium  bicarbonate  is  there  in  each  dose?) 

17.  Take  half  a  dram  of  alum  and  two  drams  of  lead  acetate, 
dissolve  separately  in  distilled  water,  mix  the  solutions,  add  dis- 
tilled water  to  make  the  total  six  ounces,  and  filter.  Directions: 
Keep  dressing  wet.  (Unless  directed  to  filter  out  the  lead  sul- 
phate formed,  the  pharmacist  would  leave  it  in  and  apply  a 
"shake-before-using"  label.) 

18.  Take  four  ounces  of  linseed  oil,  two  ounces  of  syrup  of 
wild  cherry,  the  requisite  amount  of  acacia  (the  requisite  amount 
=  q.s.),  and  water  enough  to  make  an  eight-ounce  emulsion. 
Directions:   Two  teaspoonfuls  every  four  hours. 

19.  One  ounce  each  of  compound  tincture  of  lavender, 
aromatic  spirit  of  ammonia,  and  spirit  of  chloroform.     Direc- 


PRACTICE    IN   PRESCRIPTIONS  FOR  OBJECTS    TO   BE    COUNTED      555 

tions :  A  teaspoonf ul  in  a  wineglass  of  hot  water  when  needed  for 
flatulence. 

20.  Two  ounces  of  a  solution  of  nitrate  of  silver,  10  grains  to 
the  ounce.  Put  in  a  dark  bottle,  and  label  what  it  is  (in  a  dark 
bottle  =  in  vitro  nigro  or  in  vitro  obscuro). 

The  following  is  a  facetious  prescription,  which  might  be  an 
effective  placebo : 

1$     Aquae  fontinalis gtt.  xv 

HA 

Hydrogenii  monoxidi aa  oss 

Illius  repetitae o  j 

Ejusdem 5  ij 

Nil  aliud q.  s.  ad  o  j 

M.  et  Sig. — Ten  drops  in  a  wineglass  of  water  every  three  hours — For 

nervousness! 

B.  Ointments. — Write  for: 

1.  Two  ounces  of  cold  cream.  Directions:  Rub  into  skin 
night  and  morning. 

2.  Fifteen  grains  of  salicylic  acid,  one  dram  each  of  zinc  oxide 
and  precipitated  sulphur,  and  sufficient  vaseline  (petrolatum) 
to  make  one  ounce.     Directions:   Apply  to  skin  each  night. 

3.  One  and  a  half  drams  of  oil  of  cade  and  zinc  ointment 
enough  to  make  two  ounces.  Directions:  Apply  daily  to  the 
eczematous  area  without  rubbing. 

4.  Two  drams  each  of  soft  soap  and  balsam  of  Peru  with 
\x/2  ounces  of  sulphur  ointment.  Directions:  Rub  well  into 
itching  area  twice  a  day. 

C.  Powders. — Take  2  drams  of  magnesium  oxide,  4  drams  of 
sodium  bicarbonate,  and  1  dram  of  ginger;  mix  together  and 
place  in  a  box.  Directions:  A  level  teaspoonful  with  half  a 
glass  of  water  at  eleven,  at  five,  and  at  bed-time. 

II.  PRACTICE  IN  PRESCRIPTIONS  FOR  OBJECTS  TO  BE 
COUNTED 

Write  for — 1.  Thirty  five-grain  capsules  of  quinine  sulphate. 
Directions:  Three  at  time  of  chill,  then  one  three  times  a  day 
after  eating. 

2.  Twenty-four  capsules,  each  containing  2^  minims  of 
castor  oil  and  2^  grains  of  salol.     One  every  four  hours. 

3.  Twelve  five-grain  tablets  of  phenacetin.     One  daily  at 

4  P.  M. 

4.  Eight  one-quarter-grain  tablet  triturates  of  codeine  phos- 
phate. One  for  cough  when  needed.  Have  name  of  drug  on 
label. 

5.  One  tube  of  hypodermic  tablets  of  morphine  sulphate, 
each,  yi  grain.     Put  name  on  label. 


556  PHARMACOLOGY   AND   THERAPEUTICS 

6.  Two  five-grain  blue  pills.  Take  both  at  bed-time.  Send 
also  a  bottle  of  citrate  of  magnesia. 

7.  Thirty  Blaud's  pills,  silver  coated.     One  after  each  meal. 

8.  Three  compound  cathartic  pills.  Take  all  tonight  at 
bed-time. 

9.  Twelve  glycerin  suppositories.  Insert  one  each  morning 
before  breakfast. 

10.  Six  suppositories,  each  containing  yi  grain  of  extract  of 
belladonna  and  made  with  cocoa-butter.  Insert  one  three  times 
a  day. 

11.  Three  suppositories  of  cocoa-butter,  each  containing  3 
grains  of  orthoform  and  half  a  grain  of  powdered  opium.  Make 
of  15-grain  size.     Insert  one  an  hour  before  each  irrigation. 

12.  Twenty-four  cachets,  each  containing  10  grains  of  sodium 
salicylate  and  2  grains  of  acetanilid.  One  with  water  every  three 
hours. 

13.  A  10-grain  Dover's  powder.  Take  with  a  glass  of  hot 
lemonade  after  retiring. 

14.  Six  20-grain  powders  of  bismuth  subnitrate.  One  with 
water  four  times  a  day. 

15.  Precipitated  chalk  and  sodium  bicarbonate,  10  grains  of 
each  in  a  powder.  Order  twenty  such.  One  stirred  in  half  a 
glass  of  hot  water  three  times  a  day  two  hours  after  eating. 

16.  Fifteen  20-grain  powders  of  sodium  bromide  in  waxed 
paper.     One  in  a  wineglass  of  water  morning  and  night. 

17.  Six  capsules,  each  containing  2^2  grains  of  purified  aloes, 
2  grains  of  extract  of  jalap,  5  grains  of  blue  mass,  Y^  grain  of 
extract  of  belladonna,  and  %  minim  of  oil  of  peppermint.  One 
at  bed-time  once  a  week.     (Last  two  corrective.) 

18.  Twelve  pills,  each  containing  aloin,  \  grain,  extract  of 
belladonna,  yi  grain,  strychnine  sulphate,  -fo  grain,  and  ipecac, 
2V  grain.  One  each  night.  (These  pills  are  known  to  be  ready- 
made.) 

19.  Thirty  tablets,  each  containing  rhubarb,  2  grains,  sodium 
bicarbonate,  5  grains,  ipecac,  Y/%  grain,  tincture  of  nux  vomica, 
5  minims,  fluidextract  of  cascara,  5  minims,  and  oil  of  peppermint, 
2V  minim  (or  q.  s.).  Directions:  Two  with  a  wineglass  of  water 
three  times  a  day  two  hours  after  eating.  (These  tablets  are  of 
a  standard  formula.) 

20.  Thirty  capsules,  each  containing  -^  grain  of  arsenic 
trioxide,  yi  grain  of  extract  of  nux  vomica,  and  Blaud's  pill, 
5  grains — one  after  eating. 

Miscellaneous. — Take  belladonna  plaster  and  spread  it  upon 
surgeon's  adhesive   plaster    over  a  circular  area    2   inches  in 


INCOMPATIBILITY 


557 


diameter.     (In  this  case  it  would  be  better  to  write  the  directions 
to  the  pharmacist  in  English.) 

Criticize  the  following  as  to — (i)  Completeness;  (2)  order 
and  correctness  of  names  of  ingredients;  (3)  correctness  of 
amounts;    (4)  safety  of  dosage;    (5)  directions. 

1.  1$       Spiriti  ammon.  aromat 5i 

2.  B,x     Mixt.  creta oii 

Tr.  opii 5  ii 

Subnitrate  bismuthum 5ii 

As  directed. 

INCOMPATIBILITY 

Incompatibility  between  two  substances  may  be  said  to  exist 
when  their  admixture  brings  about  physical  or  chemical  change 
other  than  simple  solution.  Such  a  change — (1)  may  be  desired 
in  a  prescription,  (2)  may  make  little,  if  any,  difference,  or  (3) 
may  be  undesirable.  A  chemic  reaction  may  result  in  a  pre- 
cipitate, may  show  merely  in  an  alteration  of  color,  or  may  make 
no  visible  change  at  all.  But  the  physician  should  know  in 
what  form  his  remedies  are  when  the  patient  takes  them. 

"  Incompatibility "  is  a  bugaboo  raised  for  the  alarm  of  the 
prospective  prescription  writer,  and  it  is  an  unnecessary  alarm. 
For,  though  a  great  many  incompatibles  for  almost  any  active 
chemical  may  be  found  in  the  laboratory,  yet  but  few  of  these 
are  ever  likely  to  be  encountered  in  a  prescription;  and  of  those 
few,  the  result  not  infrequently  makes  no  practical  change  in  the 
medicinal  value,  or  is  deliberately  desired. 

The  following  are  those  most  likely  to  be  encountered  in  the 
practical  use  of  drugs: 

I.  Incompatibility  Depending  on  Change  of  Solvent. — (a) 
Precipitate  When  Added  to  Aqueous  Liquids. — Substances  in 
alcoholic  solution  and  insoluble  in  water;  as  in  spirits,  fluid- 
extracts,  and  tinctures,  especially  resinous  ones,  like  tincture  of 
cannabis,  benzoin,  myrrh. 

(b)  Precipitate  When  Added  to  Alcoholic  Liquids. — Substances 
in  aqueous  solution  and  insoluble  in  alcohol ;  as  solutions  of  many 
salts  (sodium  sulphate,  ammonium  chloride)  and  mucilage  of 
acacia.  Mere  insolubility,  as  of  oils  or  bismuth  subnitrate  in 
water,  makes  these  really  incompatible  with  the  solvent;  but 
such  are  considered  under  the  head  of  "solubility." 

II.  Chemic  Incompatibility. — Rule  1 :  Acids  and  salts  of 
acid  reaction  are  incompatible  with  alkalies  and  salts  of  alkaline 
reaction  and  the  halogen  salts. 

Rule  2:  Highly  oxidized  substances,  like  chromium  trioxide 
(chromic  acid),  potassium  permanganate,  and  potassium  chlorate 


558  PHARMACOLOGY  AND   THERAPEUTICS 

are  decomposed  by  organic  matter.  Potassium  permanganate 
in  solution  turns  brown ;  dry  potassium  permanganate  or  chromic 
acid  may  take  fire  or  explode.  Potassium  chlorate,  when  rubbed 
with  sulphur,  hypophosphites,  ammonium  chloride,  tannic  acid 
or  other  organic  substance,  will  explode  violently. 

Rule  3:  Silver  nitrate  is  incompatible  with  organic  material 
and  turns  to  black  oxide  or  black  metallic  silver.  With  chlorides 
or  hydrochloric  acid  it  forms  the  insoluble  silver  chloride. 

Rule  4:  Mild  mercurous  chloride  (calomel)  is  incompatible 
with  sodium  carbonate  and  lime-water.  With  the  latter  it  makes 
a  black  precipitate  of  mercurous  hydroxide,  and  forms  "black 
wash,"  sometimes  employed  as  an  application  to  venereal  sores. 

Calomel  is  insoluble  in  water  or  alcohol,  comparatively  inert 
chemically,  and  bland  to  tissues. 

Rule  5:  Corrosive  mercuric  chloride  (corrosive  sublimate)  is 
incompatible  with  iodides,  many  metallic  salts,  alkaloidal  salts, 
tannic  acid,  lime-water,  and  albumin. 

With  excess  of  lime-water  it  makes  a  yellow  precipitate  of 
mercuric  oxide,  and  forms  "yellow  wash,"  employed  as  an 
application  to  venereal  sores.  When  the  mercury  salt  is  in  excess, 
the  precipitate  is  red  oxychloride. 

With  soap,  as  on  the  surgeon's  hands,  its  antiseptic  power  is 
destroyed. 

With  potassium  iodide  it  forms  mercuric  biniodide — 2  KI  + 
HgCl2  =  2  HC1  +  Hgl2.  The  iodide  is  of  a  brilliant  scarlet 
and  dissolves  in  excess  of  the  potassium  iodide.  These  two  salts 
are  often  prescribed  together  to  form  the  biniodide. 

In  albumin,  as  in  white  of  egg  or  milk,  we  have  the  antidote 
when  the  drug  is  swallowed. 

Rule  6:  Lead  acetate  decomposes  alum  and  other  sulphates 
and  the  iodides,  and  tends  to  precipitate  many  organic  substances, 
e.  g.,  glucosides,  from  their  solution. 

The  admixture  with  alum  makes  Burow's  solution.  The 
precipitate  of  lead  sulphate  should  be  filtered  off.  The  pre- 
cipitate with  the  iodide  is  lead  iodide  of  a  brilliant  yellow. 

Rule  7:  Ferric  salts — (a)  make  "ink"  with  tannic  acid;  (b) 
make  blue  to  reddish  or  purple  colors  with  compounds  of  the 
phenol  group,  such  as  phenol,  resorcin,  salicylates,  etc.;  (c) 
make  a  red  color  with  acetates,  and  (d)  form  a  dirty-brown  pre- 
cipitate with  alkalies  or  alkaline  salts. 

Rule  8:  Tannic  acid  is  incompatible  with  alkaloidal  salts, 
dry  potassium  chlorate  (explodes),  metallic  salts,  gelatin,  and 
albumin.  With  ferric  salts  it  makes  "ink."  For  salts  of  alka- 
loids and  antimony  it  is  the  local  antidote. 

It  occurs  in  many  vegetable  drugs,  and  preparations  of  these 


INCOMPATIBILITY  559 

may  not  only  precipitate  alkaloidal  salts,  but  may  change  the 
gelatin  coating  of  a  pill  or  a  gelatin  capsule  to  a  tough,  leathery, 
insoluble  substance.  Alcohol  may  prevent  the  precipitation  of 
alkaloidal  salts  by  tannic  acid,  as  in  tinctures. 

Rule  9:  Chloral  hydrate  decomposes  to  chloroform  under  the 
influence  of  strong  alkalies;  and  when  mixed  with  camphor, 
menthol,  thymol,  and  similar  substances,  undergoes  a  physical 
change  to  a  liquid. 

Rule  10:   Alkaloidal  salts  are  incompatible  with — 

(a)  Alkalies — the  precipitate  is  the  pure  alkaloid. 

(b)  Tannic  acid — the  precipitate  is  the  insoluble  tannate. 

(c)  Iodine,  iodides  and  bromides — the  precipitate  is  the 
iodide  or  bromide. 

(d)  Mercuric  bichloride — the  precipitate  is  an  insoluble 
double  salt. 

Quinine  in  addition  is  especially  precipitated  by  salicylates 
and  benzoates. 

All  these  precipitates  are  more  soluble  in  alcohol  than  water, 
so  may  not  show  in  tinctures  and  other  alcoholic  liquids. 

Rule  1 1 :  Glucosides  are  incompatible  for  the  most  part  with 
lead  acetate  and  tannic  acid,  and  are  decomposed  by  the  mineral 
acids. 


INDEX 


Abbreviations  in  prescription  writing, 

55i 

special,  in  prescription  writing,   553 
A.  B.  C.  mixture,  95 
Abortifacients,  525 
Abrin,  27 
Absinthe,  302 

cordial,  302 
Absolute  alcohol,  298 
Absorption,  to  promote,  counterirritants 

for,  73 
Acacia,  29 
Acapnia,  234 
Accelerator  system,  140 
depression,  142 
stimulation,  142 
Acetanilid,  436 

excretion,  442 

pharmacologic  action,  436-442 

poisoning  from,  442 

powder,  compound,  239,  436 

therapeutics,  443 

untoward  effects,  442 
Acetanilid-salicylic  acid,  436 
Acetanilidum,  436 
Acetates,  84 
Acetic  acid,  84 
diluted,  84 
glacial,  84 
Acetonuria  in  anesthesia,  287 
Acet-phenetidin,  436 
Acetum,  151 

definition,  41 
Acetyl-salicylic  acid,  455 
Acid,  acetanilid-salicylic,  436 

acetic,  84 
diluted,  84 
glacial,  84 

acetyl-salicylic,  455 

aconitic,  217 

agaric,  386 

arsenic,  504 

arsenous,  503 
solution  of,  504 

benzoic,  469 

boric,  466 

poisoning  from,  467 

caffeotannic,  250 

camphoric,  387 

carbolic,  471.     See  also  Phenol. 

cinchotannic,  30 

cinnamic,  469 

citric,  83,  85 

36  56r 


Acid,  citric,  effect   of,  on    clotting    of 
blood,  83 

in  typhoid  fever,  83 
crotonic,  127 
di-ethyl  barbituric,  344 
filicic,  amorphous,  for  tape-worms,  no 
formic,  84 

in  rheumatism,  84 
gymnemic,  101 
hydriodic,  diluted,  515 
hydrochloric,  81 

therapeutics,  82 
hydrocyanic,  402 

diluted,  402 

preparations,  402 

therapeutics,  403 
kinotannic,  30 
lactic,  84 
malic,  85 
nitric,  81 

action  of,  74 

dilute,  therapeutics,  83 

for  warts  or  nevi,  82 
nitrohydrochloric,  81 

diluted,  81 

therapeutics,  83 
oxalic,  85 

poisoning  from,  85 
phenyl-chinolin-carboxylic,  458 
phosphoric,  81 

dilute,  therapeutics,  83 
salicylic,  451 

absorption,  453 

administration,  455 

dose,  452 

excretion,  454 

pharmacologic  action,  452-454 

poisoning  from,  454 

preparations  and  doses,  452 

therapeutics,  455 

toxicology,  454 
succinyl  disalicylic,  456 
sulphuric,  81 

action  of,  73 

aromatic,  81 

in  night-sweats  of  tuberculosis.  83 
sulphurous,  464 
tannic,  29,  106 

and  alkaloids,  incompatibility,  22 

of  coffee,  250 

of  tea,  250 

therapeutics,  107 
tartaric,  83,  85 


562 


INDEX 


Acid,  trichloracetic,  84 

trichlorethyl-glycuronic,  341 

waters,  137 
Acidol,  83 
Acidosis  in  anesthesia,  287 

sodium  bicarbonate  in,  89 
Acids,  caustic,  73 

fruit,  85 

inorganic,  81 
action,  81 

poisoning  from,  treatment,  82 
therapeutics,  82 
toxicology,  82 

organic,  83 

plant,  and  their  salts,  20 
Acidum  aceticum,  84 

citricum,  83 

formicum,  84 

hydrochloricum,  81 

lacticum,  84 

salicylicum,  451 

sulphuricum  aromaticum,  81 

tannicum,  106 

tartaricum,  83 
Acne,  calcium  sulphide  in,  117 

potassa  sulphurata  in,  117 

precipitated  sulphur  in,  117 
Aconine,  217 
Aconite,  217 

absorption  of,  218 

administration,  221 

constituents,  217 

excretion,  220 

fluidextract,  dose,  217 

in  fevers,  221 

in  pain,  221 

in  trifacial  neuralgia,  221 

pharmacologic  action,  217-220 

poisoning  from,  220 
treatment,  221 

preparations  and  doses,  217 

Squibb's  test  for,  218 

therapeutics,  221 

tincture,  dose,  217 

toxicology,  220 
Aconitic  acid,  217 
Aconitine,  217 

dose,  217 
Aconitum,  217 

napellus,  217 
Acrinyl  sulphocyanide,  26 
Acromegaly,  pituitary  extract  in,  196 
Actinomycosis,  copper  sulphate  in,   493 

iodides  in,  518 
Active  constituents  of  drugs,  19,  20 

principles,  44 
Adalin,  345 

Addison's  disease,  epinephrine  in,  195 
Adenin,  238 
Adeps,  30 

lanas  hydrosus,  32 


Adhesions  in  abdominal  surgery,  liquid 

vaseline  to  prevent,  34 
Adjectives,  Latin,  543 
Administration,  52,  62 

by  hypodermatoclysis,  54 

by  inunction,  55 

by  mouth,  52 

by  rectum,  55 

by  skin,  55 

by  veins,  55 

channel  of,  dose  and,  51 

frequency  of,  dose  and,  52 

hypodermatic,  52 
advantages,  54 
disadvantages,  54 

intracutaneous,  54 

intramuscular,  53 

intravenous,  55 

methods,  52 

subcutaneously,  52,  53 
superficial,  54 

through  lungs  by  inhalation,  55 

time  of,  55 
dose  and,  52 
Adonidin,  dose,  151 
Adonis  vernalis,  dose,  151 
Adrenaline,  186.     See  also  Epinephrine. 
Adverbs,  Latin,  544 
.Ether,  267 
.Ethylis  carbamis,  345 

chloridum,  296 
Agar,  phenolphthalein-,  125 

as  cathartic,  115 
Agar-agar  as  cathartic,  115 
Agaric  acid,  386 

deadly,  418 

fly,  417,  418 

Agaricin,  386 

dose,  386 

in  excessive  sweating,  386 
Agaricus  campestris,  419 
Age,  dose  and,  48 
Agurin,  249 
Air,  cold,  as  circulatory  stimulant,  147 

superheated,  425 
Albolene,  liquid,  ^3,  117 

solid,  S3 
Albuminuria    after    chloroform     anes- 
thesia, 274 

after  ether  anesthesia,  274 

functional,  iron  in,  503 
Alcohol,  297 

absolute,  298 

absorption,  305 

as  anidrotic,  333 

as  antiseptic,  333 

as  cooling  lotion,  333 

as  hypnotic,  334 

as  narcotic  or  sedative,  334 

as  preventive  of  carbolic-acid  burns, 
333 


INDEX 


563 


Alcohol,  cirrhosis  of  liver  and,  308,  309 

contraindications,  334 

denatured,  298 

deodorized,  298 

diluted,  298 

elimination,  323 

ethyl,  297 

food  value,  313-319 

grain,  297 

habit,  cure  of,  329 

in  convalescence,  334 

in  debility,  334 

in  fever,  334 

in  gout,  324 

in  shock,  334 

in  trigeminal  neuralgia,  333 

methyl,  335 

narcosis,  stages,  313 

pathologic  effects  on  organs,  330 

pharmacologic  action,  303-325 

poisoning  from,  325 
after-effects,  326 
treatment,  326 

preparations,  298 

salicyl,  25 

stupor  from,  325 

therapeutics,  333 

to  harden  skin,  333 

to  prevent  or  check  a  cold,  334 

tolerance,  332 

toxicology,  325 

wood,  335 
Alcoholic  liquids,  41 
Alcoholism,  acute,  325 
treatment,  326 

chronic,  327 

Korsakoff's  psychosis  in,  327 
treatment,  328 
Ales,  299 

Alkalies  and  alkaloids,  incompatibility, 
22 

caustic,  73,  86 

mild,  86 
Alkaline  saline  waters,  137,  138 

waters,  137,  138 
Alkaloidal  salts,  21 

solubility  of,  21 
Alkaloids,  21 

and  alkalies,  incompatibility,  22 

and  bromides,  incompatibility,  22 

and  iodides,  incompatibility,  22 

and  iodine,  incompatibility,  22 

and    mercuric    chloride,    incompati- 
bility, 22 

and  tannic  acid,  incompatibility,  22 

artificial,  23 

incompatibles,  22 

nomenclature,  21 

occurrence,  23 

opium,  352 

physical  character,  22 


Alkaloids,  pure,  21 
solubility  of,  21 

salts,  differences  in    physiologic    ac- 
tions, 24 

solubility  of,  21 

taste  of,  22 
Allyl  sulphocarbamide,  75 

sulphocyanide,  26 
Almond,  bitter,  oil  of,  25,  402 
spirit  of,  403 

oil,  30 

water,  bitter,  403 
Aloes,  123 

and  iron,  123 

and  myrrh,  pills  of,  123 
tincture  of,  123 

dose,  123 

extract  of,  123 

preparations,  123 

purified,  123 

tincture  of,  123 
Aloin,  26,  123 
Aloinum,  123 
Alum,  498 

burnt,  498 

therapeutics,  498 

waters,  137 
Alumen,  498 

exsiccatum,  498 
Aluminis,  498 
Aluminium,  498 

acetate,  solution  of,  498 

as  antiseptic  and  disinfectant,  466 
Aluminum,  498 
Alypine,  398 
Amanita  muscaria,  417,  418 

phalloides,  27,  418 

toxin,  27 

verna,  418 
Amaroids,  26 
Amaurosis,  quinine,  447 
Amblyopia,  quinine,  447 

tobacco,  410 
Amebic  colitis,  quinine  in,  449 

dysentery,  emetine  chloride  in,  524 
ipecac  in,  524 
American  hellebore,  222 

wormseed,  109 
Aminopurins,  238 
Ammonia,  203,  204 

absorption  of,  205 
effects  after,  20S 

administration,  208 

as  antacid  carminative,  208 

as  counterirritant,  208 

as  expectorant,  208 

as  reflex  circulatory  stimulant,  208 
respiratory  stimulant,  208 

chloride,    209.     See  also  Ammonium 
chloride. 

contraindications,  208 


564 


INDEX 


Ammonia  liniment,  204 
liver  in  disposal  of,  205,  206 
muriate,  209 

pharmacologic  action,  204-207 
poisoning  from,  207,  208 

treatment,  208 
preparations,  204 
spirit,  204 
therapeutics,  208 
toxicology,  207 
water,  204 

poisoning  from,  207,  208 
stronger,  204 
Ammoniated  tincture  of  valerian,  100 
Ammonium,  203 
acetate,  210 

solution  of,  1 20 
benzoate,  210 
bromide,  210 
carbonate,  204 
chloride,  209 

absorption  of,  209 
action  of,  209 
excretion  of,  209 
in  acute  pharyngitis,  210 
in  bronchitis,  210 
in  laryngitis,  210 
therapeutics,  210 
iodide,  210 
preparations,  204 
salicylate,  210 
valerate,  210 
Amorphous  filicic  acid  for  tape-worms, 

no 
Amygdala  amara,  402 
Amygdalin,  25 
Amyl  nitrite,  225 
dose,  225 
effect,  227 

in  angina  pectoris,  230 
in  chloroform  collapse,  231 
Amylene  hydrate,  346 
Amylis  nitris,  225 
Amylum,  28 

Analgesia,  spinal,  in  shock,  234 
with  cocaine,  389,  390,  396 
with  stovaine  and  strychnine,  390 
Analgesic  antipyretics,  435 
administration,  443 
in  pain,  443 

pharmacologic  action,  436-442 
therapeutics,  443 
to  overcome  fever,  443 
toxicology,  442 
Anaphylaxis,  atropine  in,  383 
Anatomic   material,   preservatives   for, 

481 
Anemia,  cholesterin  in,  32 
iron  in,  503 

pernicious,  cholesterin  in,  32 
transfusion  of  blood  in,  212 


Anesthesia,  acetonuria  in,  287 
acidosis  in,  287 
Bier's  vein,  397 

by  intratracheal  insufflation,  292 
chloroform,  277,  283 
advantages,  284 
albuminuria  after,  274 
amount  necessary  to  produce,  290 
closed  inhalers  for  administration, 

290 
collapse  in,  camphor  in,  294 

treatment,  294 
contraindications,  287 
dangers,  284-287 
delayed  poisoning  from,  2S6 
drop  method  of  administration,  289 
intravenous,  292 
preventive  measures  in,  287 
cocaine  chloride,  395 
collapse  in,  treatment,  294 
colonic,  291 

cyanosis  in,  treatment,  293 
effect,  on  immunity,  288 

on  infections,  288 
ether,  277 

administration  of  sodium  bicarbon- 
ate before,  283 
after-effects,  280 
albuminuria  after,  274 
amount  necessary  to  produce,  290 
closed   inhalers   for  administering, 

289 
collapse  in,  280 

saline  infusion  in,  294 
treatment,  294 
conjunctivitis  after,  281 
danger-signs,  280 
diluting  with  oxygen,  282 
distention   of   stomach   and  intes- 
tines after,  281 
drop  method  of  administration,  289 
feeding    with    carbohydrates    and 

water,  282 
first  stage,  278 
fourth  stage,  279 
having  stomach  empty,  282 
helpful  measures  in,  282 
indications,  283 

injection  of  atropine  sulphate  in,  281 
intravenous,  292 
kidneys  after,  281 
nausea  after,  280 

open-cone  method    of  administra- 
tion, 289 
pain  in  back  after,  281 
post-operative  gastric  or  intestinal 

paralysis  after,  281 
preliminary  administration  of  sed- 
ative drugs,  282 
anesthetization  with  chloroform, 
282 


INDEX 


565 


Anesthesia,  ether,  preliminary  anesthet- 
ization with  ethyl  chloride, 
282 
with  nitrous  oxide,  282 
preventive  measures  in,  282 
reassuring  patient,  282 
recovery  from,  280 
respiratory  troubles  after,  281 
second  stage,  278 
sore  tongue  after,  281 
third  stage,  279 
thirst  after,  281 
untoward  sequels,  281 
vomiting  after,  280 
warming  vapor,  282 
ethyl  bromide,  297 

chloride,  297 
false,  280 

infiltration,  Schleich's,  399 
intravenous,  292 
Bier's,  402 
local,  402 
paraldehyd,  346 
with  cocaine,  397 
laughing-gas,  295 
nitrous  oxide,  295 
objects,  295 
pulse  in,  294 
rectal,  291 

Schleich's  infiltration,  399 
scopolamine-morphine,  385 
spinal,  in  strychnine  poisoning,  264 
with  cocaine,  389,  390,  396 
with  stovaine  and  strychnine,  390 
therapeutics,  295 
to  prolong,  epinephrine  for,  195 
untoward  symptoms,  treatment,  293 
with  Epsom  salt,  400,  401 
with  magnesium  sulphate,  400,  401 
Anesthesin,  399 
Anesthetics,  administration,  288 

general,  267 
Aneurysm,  gelatin  in,  37 

of  aorta,  digitalis  in,  185 
Angina  pectoris,  amyl  nitrite  in,  230 

Hoffmann's  anodyne  in,  271 
Anhydrotics,  386 
Anidrotics,  386 
Animal  charcoal,  102 
purified,  102 
derivatives,  special,  37 
experimentation,  58 
fats,  30 
oils,  30 
Anodyne,  Hoffmann's,  dose,  267 
in  angina  pectoris,  271 
in  dyspnea,  267 
in  hysteria,  271 
in  spasm,  271 
therapeutic  uses,  271 
Antacids,  86 


Antacids  as  antemetics,  104 

not  of  alkaline  reaction,  94 

of  alkaline  reaction,  86 
Antagonists,  57 
Antemetics,  104 
Anterior   poliomyelitis,  epinephrine  in, 

i9S 
Anthelmintics,  107 
Anthracene  derivatives,  122 
action  on  bowel,  122 
therapeutics,  123 
Anti-bitters,  101 
Anti-diarrheics,  136 
Antidotes  in  poisoning  from  inorganic 

acids,  82 
Antiformin,  464 
Antihysterics,  369 
Anti-malarial  antipyretics,  444 
Antimony,  512 

and  potassium  tartrate,  512 

in  trypanosomiasis,  513 

pharmacologic  action,  512,  513 

poisoning,  513 

preparations  and  doses,  512 

wine  of,  512 
Antiphlogistine,  71 
Antipyretic  drugs,  435 
Antipyretics,  434 

analgesic,  435 

administration,  443 

in  pain,  443 

pharmacologic  action,  436-442 

therapeutics,  443 

to  overcome  fever,  443 

toxicology,  442 

anti-malarial,  444 

antirheumatic,  451 
Antipyrina,  435 
Antipyrine,  24,  435 

excretion,  442 

in  chorea,  443 

in  diabetes,  443 

in  nasal  hemorrhage,  443 

in  tuberculous  laryngitis,  443 

in  whooping-cough,  443 

pharmacologic  action,  436-442 

poisoning  from,  442 

salicylate,  436 

therapeutics,  443 

untoward  effects,  442 
Antirheumatic  antipyretics,  451 
Antiseptic  iodine  compounds,  465 

solution,  470 
Antiseptics,  459 

classification,  462 

tests  for  value,  460 
Antispasmodics,  369 
Antisyphilitics,    mercurv   preparations, 

485 
Antithyroid  preparations,  522 
Antithyroidin,  522 


566 


INDEX 


Antitoxins,  preservatives  for,  481 
Anus,  diseases  of,  cocaine  in,  396 
Aorta,  aneurysm  of,  digitalis  in,  185 
Aortic  insufficiency,  digitalis  in,  183 

stenosis,  digitalis  in,  184 
Aortitis,  digitalis  in,  185 
Aperient,  113 
Aperitol,  125 
Apocodeine,  104 

as  cathartic,  116 
Apocynein,  151 
Apocynin,  151 
Apocynum,  151 

dose,  151 
Apolysin,  436 
Apomorphine,  24 

chloride,  103 
Apothecaries'  system,  prescriptions  of, 

535 

weights  and  measures,  43 
exact  equivalents,  44 
Appalache  tea,  239 
Appetite  juice,  100,  306 
Apple,  bitter,  poisoning  from,  126 

cider,  300 
Apple-brandy,  301 
Aqua.  40 

ammonia?,  204 
fortior,  204 

hydrogenii  dioxidi,  463 
Aqueous  liquids,  40 
Arabinose,  29 
Areas,  Head's,  69 
Argentum,  496 
Argyria,  498 

conjunctival,  498 
Argyrol,  497 
Arhythmia  from  digitalis,  156 

phasic,  from  digitalis,  166 

sinus,  digitalis  in,  179 
Aristol,  465,  470 
Aromatic  bitters,  101 

elixir,  99,  302 

sulphuric  acid,  81 
Aromatics,  95 

for  prescription,  539 

pharmacologic  action,  95-97 
Arrowroot  starch,  29 
Arsacetin,  504 
Arsenic,  503 

absorption,  506 

acid,  504 

administration,  511 

excretion,  507 

iodide,  504 

organic  compounds,  504 

pharmacologic  action,  505-508 

poisoning,  acute,  508 

iron  as  antidote,  499,  509 
treatment,  509 
chronic,  509 


Arsenic    poisoning,  chronic,  treatment, 

5io 
cumulative,  510 
preparations  and  doses,  503 
therapeutics,  510 
tolerance,  507 
toxicology,  508 
trioxide,  503 
white,  503 
Arsenical  waters,  137 
Arsenic-eaters,  507 
Arseniureted  hydrogen,  508 
Arsenophenylglycin,  504 
Arsenous  acid,  503 

solution  of,  504 
Arsenum,  503 
Arterial  dilators,  225 
pressure,  145 

raising,   mechanical   measures   for, 

210 
regulators  of,  145 
Arteries,  blood  in,  decrease  of,  causes, 

139 
increase  of,  causes,  139 
changes  in  caliber,  143 
conditions  of,  influence,  on  usefulness 

of  digitalis,  182 
connective-tissue    changes    in,    from 

epinephrine,  191 
contraction  of,  143,  144 
coronary,  action  of  digitalis  on  circu- 
lation through, 167 
constriction  of,  from  digitalis,  167 
cutaneous,  action  of  digitalis  on  cir- 
culation through, 170 
dilatation  of,  143,  144 
measures    for    increasing   volume   of 

blood  in,  211 
pulmonary,    action    of    digitalis    on 

circulation  through,  170 
systemic,  action  of  digitalis  on  circu- 
lation through, 168 
Arterioles  as  regulators  of  arterial  pres- 
sure, 145 
cutaneous,  caliber  of,  144 
Arteriosclerosis,  digitalis  in,  185 

from  smoking,  411 
Arthritis,  dry,  vaseline  in,  34 

rheumatoid,  thyroid  gland  in,  522 
Artificial  alkaloids,  23 
emulsion,  41 
leech,  233 

respiration   in   strychnine   poisoning, 
264 
Asagraea  officinalis,  222 
Ascaris  lumbricoides,  remedies  for,  108 
Aspergillus  oryzae,  80 
Aspidium,  oleoresin  of,  for  hookworms, 
109 
for  tape-worms,  no 
poisoning  from,  no 


INDEX 


567 


Aspidosperma  as  expectorant,  522 
Aspirin,  455 

poisoning  from,  456 
Assay  processes,  44,  45 
Assayed  drugs,  45 
Asthma,  bronchial,  calcium  in,  94 
epinephrin  in,  195 

powders,  231 

spasmodic,  lobelia  in,  405 
sparteine  sulphate  in,  405 
stramonium  in,  384 

tobacco  in,  406 
Astringents,  105 

doses,  106 

metallic,  105 

preparations,  106 

tannic-acid,  106 

vegetable,  106 
Ataxia,  locomotor,  strychnine  in,  265 
Atophan, 458 

in  gout,  458 

in  uric-acid  diathesis,  458 
Atoxyl,  504 

Atropa  belladonna,  370 
Atrophy,  pigment,  in  morphinism,  364 
Atropine,  370 

absorption,  373 

administration,  381 

as  preliminary  to  general  anesthesia, 

383 
elimination,  380 
in  anaphylaxis,  383 
in  diseases  of  eye,  382,  383 
in  exophthalmic  goiter,  383 
in  hyperthyroidism,  383 
in  intestinal  obstruction,  382 
in  narcotic  poisoning,  376 
in  pain,  379 

in  spasmodic  nervous  diseases,  383 
pharmacologic  action,  372-380 
poisoning  from,  380 

treatment,  381 
solubility  of,  21 
sulphate,  371 

injection,  in  ether  anesthesia,  282 

solubility  of,  22 
therapeutics,  382 

to  check  excessive  vagus  action,  383 
to     depress     sensory    nerve-endings, 

392  . 
to  diminish  secretion,  381,  382 
to  relax  overcontracted  smooth  mus- 
cle, 382 
to  stimulate  respiration,  383 
tolerance,  381 
toxicology,  380 
Auricular  fibrillation,  digitalis  in,  179 
from  digitalis,  159 
flutter,  digitalis  in,  181 
Auriculoventricular    bundle,    action    of 
digitalis  on  circulation  through,  161 


Back,  pain  in,  after  ether  anesthesia, 

281 
Bacteria,  action  of  camphor  on,  199 
Baking  soda,  86 
Balsam  gauze,  469 

of  Peru,  469 
Balsams,  36 
Barbaloin,  124 
Barii,  198 
Barium,  198 

action  of,  198 

poisoning  from,  198 
Basham's  mixture,  210,  500 
Bastedo's  rule  for  doses  for  children,  548 
Bath,  bed-,  435 

cold,  434 

electric,  420 

hot-air,  420 

Nauheim,    as    circulatory  stimulant, 

147 

Russian,  419 

tub-,  434 

Turkish,  419 

vapor,  420 
Beck's    method    of    treating    chronic 

sinuses  or  tuberculous  cavities,  495 
Bed-bath,  435 
Beebe's  serum,  522 
Beers,  299 
Beeswax,  33 
Belladonna,  370,  371 

administration,  381 

compound  laxative  pills,  372 

constituents,  370 

dose,  371 

elimination,  380 

group, 370 

pharmacologic  actions,  372-380 
preparations  and  doses,  371 

jag,  377 

occurrence,  370 

ointment,  372 

pharmacologic  action,  372-380 

plaster,  372 

poisoning  from,  380 
treatment,  381 

therapeutics,  381 

to  depress  sensory  nerve-endings,  382 

to  diminish  secretion,  381,  382 

tolerance,  381 

toxicology,  380 
Benedictine,  302 
Benzaconine,  217 
Benzaldehyde,  99 
Benzin,  t>3 
Benzinum,  ^t, 
Benzoic  acid,  469 
Benzoin,  469 
Benzosulphimid,  66 

Benzoyl  ester  of  pseudo-tropine  chlor- 
ide, 398 


568 


INDEX 


Benzoyl-tetramethyl-diamino-ethyl-iso- 

propylic  alcohol  chloride,  398 
Berberine,  530 
Bernard's  experiment  with  strychnine, 

256 
Beta-eucaine  chloride,  397 

lactate,  397 
Betanaphthol,  470 

for  hookworms,  109 
Beverages,  caffeine,  249 
Bhang,  368 
Bichloride  of  mercury  as  disinfectant, 

484 
Bier's  vein  anesthesia,  402 
Bile  salts,  117 
Biliousness,  calomel  in,  121 
Bimuriate  of  quinine  and  urea,  444 
Bismuth,  494 

as  antiseptic  and  disinfectant,  466 

in  gastric  irritation,  495 

in  intestinal  irritation,  495 

in  nausea,  495 

in  vomiting,  495 

milk  of,  495 

poisoning,  494 

subcarbonate,  494 

subgallate,  494 

subnitrate,  494 

and  vaseline  in  chronic  sinuses  or 
tuberculous  cavities,  495 

therapeutics,  495 
Bismuthum,  494 
Bites,  dog-,  caustics  for,  74 
Bitter  almond,  oil  of,  25,  402 
spirit  of,  403 
water,  403 

apple,  poisoning  from,  126 

principles,  26 
Bitters,  100 

anti-,  101 

aromatic,  101 

simple,  101 
Black  snakeroot,  458 

tea,  250 

wash,  485 
Blackwater  fever,  quinine  in,  450 
Bladder,  action  of  epinephrine  on,  193 

catheterization  in  strychnine  poison- 
ing, 264 

disinfectants,  483 
Blaud's  pills,  500 
Bleaching-agents,  463 
Bleeding    from    nose,    counterirritants 

for,  73 
Blindness  from  methyl  alcohol,  356 

quinine,  447 
Blister,  fly-,  72 
Blistering,  68 
Blocking  nerves,  234 
Blood,   capillary    flow,  alterations    in, 

139 


Blood,  clotting  of,  effect  of  calcium  on, 

93 
of  citric  acid  on,  83 

effect  of  iron  on,  501 

in  arteries,  decrease  of,  causes,  139 
increase  of,  causes,  139 

in  heart,  output  of,  influences  affect- 
ing, 139 

transfusion  of,  211 

conditions  indicating,  212 
in  shock  and  collapse,  237 

volume  of,  in  arteries,  measures  for 
increasing,  211 
measures  for  decreasing,  231 
Blood-letting,  231 
Blood-pressure,  remedies  which  lower, 

217 
Blood-supply  of  brain,  144 

of  heart,  144 
Blood-vessels,  143 
Blue  ointment  as  antiseptic,  485 
Body-heat,  methods  of  raising,  419 
Bone-black,  102 
Borax  as  preservative,  466 
Boric  acid,  466 

poisoning  from,  467 
Boroglycerin,  glycerite  of,  467 
Borosal,  467 
Bowel  splint,  354 
Bradycardia  from  digitalis,  156 
Brain,  blood-supply,  144 

wet,  331 
Brandy,  301 

French,  301 

milk-punch,  302 
Breathing,  depressed,  oxygen  in,  534 
British  gum,  29 

Brom-di-ethyl-acetyl-carbamide,  345 
Bromides,  347 

absorption,  347 

and  alkaloids,  incompatibility,  22 

dose,  347 

elimination,  348 

in  cardiac  excitability,  351 

in  convulsions,  350 

in  nervous  irritability,  350 

in  pain,  350 

in  sexual  hyperesthesia,  350 

in  strychnine  poisoning,  264 

in  vomiting,  350 

pharmacologic  action,  347-349 

poisoning  from,  acute,  349 
chronic,  350 
treatment,  350 

rash  from,  349 

therapeutics,  350 

to  quiet  reflexes,  351 

toxicology,  349 
Bromine,  465 

waters,  137 
Bromipin,  351 


INDEX 


569 


Bromipin  in  epilepsy,  351 

Bromism,  350 

Bromoform,  351 

Bromural,  345 

Bronchi,  disinfectants,  483 

Bronchial  asthma,  calcium  in,  94 
epinephrin  in,  195 
muscles,  action  of  strychnine  on,  261 

Bronchitis,  ammonium  chloride  in,  210 

Broom,  404 

Brown  mixture,  523 

Brucine,  254 

Bum  mixture,  271 

Bundle,   auriculoventricular,  action   of 
digitalis  on  circulation  through,  161 

Burns,    carbolic-acid,    alcohol    as   pre- 
ventive, ^^ 

Burnt  alum,  498 
magnesia,  90 

Burow's  solution,  489,  498 

Butter,  30 
cocoa-,  30 

Butyl  chloral  hydrate  in  trifacial  neu- 
ralgia, 343 


Cacao-butter,  30,  253 
Cade,  oil  of,  35 
Caffeina,  239 
citrata,  239 

effervescens,  239 
Caffeine,  239 
absorption,  240 
administration,  249 
allies,  249 
and  sodium  benzoate,  239 

salicylate,  239 
as  emergency  heart  stimulant,  248 
as  stimulant,  248 
as  tonic,  248 
beverages,  249 
citrated,  239 

dose,  239 

effervescent,  dose,  239 
diuresis,  244,  246 
dose,  239 
excretion,  243 
group,  238 
in  collapse,  247 
in  dropsy,  248 

pharmacologic  action,  240-247 
poisoning  from,  247 

treatment,  247 
preparations  and  doses,  239 
strychnine  and,  comparison  of  action, 

260 


therapeutics,  247 
toxicology,  247 

Caffeol,  249,  250,  251 

Caffeon,  249 

Caffeotannic  acid,  250 


Calabar  bean,  411 
Calabarine.  412 
Calamine,  493 

lotion,  493 
Calcii  carbonas  prsecipitatus,  91 
Calcium,  90 

carbonate,  91 

chloride,  91 

effect  on  coagulation  of  blood,  93 

glycerophosphate,  514 

hydroxide,  91 

in  bronchial  asthma,  94 

in  clotting  of  milk  by  rennet,  93 

in  hemorrhage,  93 

in  nervous  diseases,  94 

in  serum  sickness,  94 

in  tetany,  92,  94 

lactate,  91 

pharmacologic  action,  91-93 

poisoning,  94 

preparations,  90 

relation  of,  to  body  metabolism,  91 

sulphide  in  acne,  117 

therapeutics,  93 
Calisaya,  444 
Calomel,  120 

administration,  121 

diuretic  action,  430,  486 

in  biliousness,  121 

in  croupous  laryngitis,  486 

in  sluggish  liver,  121 

therapeutics,  121 
Calx  sulphurata  for  blood  in  acne,  117 
Camphor,  99,  199 

absorption  of,  200 

administration.  203 

as  anti-diarrheic,  203 

as  antipyretic,  203 

as  carminative,  203 

as  cooling  application,  203 

as  counterirritant,  203 

as  stimulant  and  antiseptic  to  mucous 
membranes,  203 

cerate,  199 

chloral-,  338 

elimination  of,  202 

ice,  199 

in  chloroform  collapse,  294 

in  colds,  203 

in  colic,  203 

in  collapse,  203 

in  fever,  203 

in  flatulence,  203 

in  hysteric  conditions,  203 

in  nervous  instability,  203 

in  pneumonia,  203 

in  shock,  203 

liniment,  199 

local  uses,  203 

monobromated,  199 

pharmacologic  action,  199-202 


57o 


INDEX 


Camphor,  poisoning  from,  202 
preparations  and  doses,  199 
spirit  of,  dose,  199 
therapeutics,  203 
toxicology,  202 
water,  dose,  199 
Camphora,  199 

monobromata,  199 
Camphorated  tincture  of  opium,  dose, 

352 
Camphoric  acid,  387 
Canadine,  530 
Cane-sugar,  28 
Cannabinine,  368 
Cannabinol,  368 
Cannabis  indica,  368 
constituents,  368 
dose,  368 
extract,  dose,  368 
fiuidextract,  dose,  36S 
in  pain,  369 

pharmacologic  action,  368 
preparations  and  doses,  368 
therapeutics,  368 
tincture,  dose,  368 
sativa,  368 
Cantharides,  72 
Cantharis,  72 

vesicatoria,  72 
Capillaries,  contraction  of,  145 

dilatation  of,  145 
Capillary  flow  of  blood,  alterations  in, 

139 
Carbo  animalis,  102 
Carbohydrates,  27 

Carbolic  acid,  471.     See  also  Phenol. 
Carbon  dioxide  in  collapse,  237 
in  shock,  237 
therapeutics,  74 
monoxide,  532 
poisoning,  532 
acute,  533 
chronic,  533 

transfusion  of  blood  in,  210 
treatment,  533 
Cardiac  depressants,  217 

excitability,  bromides  in,  351 
muscle,  action  of  digitalis  on  circula- 
tion through, 157 
Cardio-inhibitory  nerve,  141 
Carica  papaya,  80 
Carminatives,  95 
absorption  of,  96 
as  anesthetics,  98 
as  antemetics,  104 
as  anthelmintics,  98 
as  anti-asthmatics,  98 
as  anticolics,  97 
as  antihysterics,  98 
as  antirheumatics,  98 
as  antiseptics,  98 


Carminatives   as   bronchial  stimulants, 

98 
as  correctives,  97 
as  counterirritants,  98 
as  diuretics,  98 
as  emmenagogues,  98 
as  odors  and  flavors,  97 
as  stimulants  in  chronic  skin  diseases, 
98 

to  growth  of  hair,  9S 

to  mucous  membranes  of  nose  and 
throat,  98 
as  urinary  antiseptics,  98 
compound  tinctures,  100 
doses,  100 
elimination  of,  96 
elixirs,  99 
fluidextracts,  100 
in  leprosy,  98 
in  tympanites,  97 
pharmacologic  action,  95-97 
poisoning  from,  97 
preparations,  99 
simple  aromatic  tinctures,  99 
spirits,  99 
therapeutics,  97 
tinctures,  compound,  100 

simple  aromatic,  99 
volatile  oils  of,  official,  99 
waters,  99 
Cascara  sagrada,  1 24 
Castile  soap,  30,  31,  118 
Castor  oil,  31,  118 

administration,  119 

therapeutics,  119 
Castor-lax,  119 
Cataplasma,  definition,  42 

kaolini,  71 
Cathartic  enema,  134 

as  softening  agent,  134 
measures,  113 

agar-agar,  115 

apocodeine,  116 

cereals,  115 

drugs,  116 

exercises,  114 

fixed  oils,  118 

foods,  114 

fruits,  115 

glycerin,  118 

habit  formation,  113 

massage,  114 

pararegulin,  116 

phenolphthalein-agar,  115 

physostigmine,  116 

regulin,  115 

response  to  desire  to  defecate,  1 14 

salads,  115 

soaps,  118 

vegetable,  115 
mercurials,  120 


INDEX 


571 


Cathartic  pills,  compound,  128 

vegetable,  128 
Cathartics,  no 
acting  by  selective  affinity,  116 
cramp  from,  113 
griping  from,  113 
saline,  128 

in  constipation,  objections,  133 
doses,  129 

Moreau's  loop  and,  132 
pharmacologic  action,  129-133 
preparations,  129 
therapeutics,  133 
time  to  give,  55 
Catheterization  of  bladder  in  strychnine 

poisoning,  264 
Caustic  acids,  73 
alkalies,  73,  86 
lunar,  496 
metallic  salts,  73 
Caustics,  73 
therapeutics,  74 
toxicology,  74 
Cauterize,  74 
Cautions,  62 

Cecum  as  factor  in  defecation,  112 
Cells,  effect  of  drugs  on,  56 
Central  emetic,  103 
nervous  stimulants,  238 

system,  remedies  acting  on,  238 
which  depress,  266 
Cephaeline,  523 
Cephaelis  acuminata,  523 

ipecacuanha,  523 
Cera  alba,  33 

flava,  33 
Cerate,  definition,  43 
Ceratum,  definition,  43 
Cereals  as  cathartic  measure,  115 
Cerebral   circulation,   adequate,   main- 
tenance of,  145 
congestion,  counterirritants  for,  73 
depression  from  hypnotic  drugs,  337, 
.338 
Cerium,  495 

in  nausea  and  vomiting,  495 
oxalate,  495 
Cetaceum,  33 
Cetyl  palmitate,  33 
Cevadilline,  222 
Cevadine,  222,  223 

action,  223 
Chalk,  drop-,  91 
precipitated,  91 
prepared,  91 
Chalybeate  waters,  137 
Charas,  368 
Charcoal,  102 
animal,  102 

purified,  102 
wood-,  102 


Charta,  definition,  42 

sinapis,  72 
Chartreuse,  302 
Chemic  incompatibility,  557 

percentage  liquids,  38 
Chemistry,  pharmaceutic,  18 
Chenopodium  for  round-worms,  109 
Cherry,  wild,  fluidextract  of,  402 

infusion  of,  402 

syrup  of,  402 
Cherry-gum,  29 
Chewing-tobacco,  405 
Children,  doses  for,  48 

Bastedo's  rule,  548 

Cowling's  rule,  549 
Chloral  hydrate,  321,  338 

absorption,  339 

administration,  343 

as  circulatory  depressant,  342 

as  hypnotic,  342 

as  motor  depressant,  342 

cautions,  342 

contraindications,  342 

elimination,  340 

in  obstetrics,  342 

in  pain,  342 

in  strychnine  poisoning,  264 

in  toothache,  342 

pharmacologic  action,  338-341 

poisoning  from,  acute,  341 
chronic,  342 

therapeutics,  342 

toxicology,  341 

untoward  effects,  341 
Chloralamide,  343 
Chloral-camphor,  338 

in  pain,  203 
Chloralformamidum,  343 
Chloralism,  342 
Chloralum  hydratum,  338 
Chlorbutanol,  343,  399 
Chloretone,  343,  399 
Chloride  of  lime,  464 

of  quinine  and  urea,  444 
Chlorinated  lime,  464 
Chlorine,  464 
water,  464 
Chloroform,  271 
administration,  289 
anesthesia,  277,  283 

advantages,  284 

albuminuria  after,  274 

amount      necessary     to     produce, 
290 

closed  inhalers  for  administration, 
290 

collapse  in,  amyl  nitrite  in,  231 
treatment,  294 

contraindications,  287 

dangers,  284-287 

delayed  poisoning  from,  286 


572 


INDEX 


Chloroform  anesthesia,  drop  method  of 
administration,  289 

intravenous,  292 

preventive  measures  in,  287 
as  antemetic,  275 
as  antibysteric,  275 
as  carminative,  275 
as  rubefacient,  275 
dose,  271 
elimination,  274 
emulsion,  dose,  271 
for  tape-worms,  1 10 
habit,  275 
in  colic,  275 
in  flatulence,  275 
in  pain,  275 
in  toothache,  275 
in  vomiting,  275 
inhalations  in  strychnine  poisoning, 

liniment,  271 

pharmacologic  action,  272-274 

poisoning,  delayed,  286 

preliminary  administration,  in  ether 
anesthesia,  282 

spirit,  dose,  271 

therapeutics,  275 

water,  dose,  271 
Chloroform-acetone,  343 
Chloroformum,  271 

preparations  and  doses,  271 
Chlorosis,  iron  in,  503 
Chocolate,  249,  252 
Cholagogue,  113 
Cholera  mixture,  Sun,  136 

saline  infusion  in,  216 
Cholesterin,  32 

in  anemia,  32 

in  pernicious  anemia,  32 
Chorea,  antipyrine  in,  443 
Chromium  trioxide,  74 
Chrysarobin,  26,  75 

in  psoriasis,  76 
Ciders,  300 

Cigarette  smoking,  409,  410 
Cimicifuga,  458 

in  gout  and  rheumatism,  458 
Cinchona,  444 

administration,  451 

compound  tincture  of,  101 
dose,  444 

constituents,  444 

fluidextract,  dose,  444 

pharmacologic  action,  445-449 

preparations  and  doses,  444 

rubra,  444 

tincture,  dose,  444 
Cinchonidine,  444 
Cinchonine,  444 

sulphate,  444 
Cinchonism,  449 


Cinchonism,  treatment,  449 
Cinchotannic  acid,  30 
Cinchotannin,  30 
Cinnaldehyde,  99 
Cinnamic  acid,  469 
Cinnamomum  camphora,  199 
Cinnamyl-cocaine,  387 
Circulation,  cerebral,  adequate,  main- 
tenance of,  145 
coronary,  142 
failure  of,  oxygen  in,  534 
physiology  of,  139 
pulmonary,  145 

remedies  whose  chief  action  is  upon, 
138 
Circulatory  organs,  functions,  139 

stimulants,  147 
Cirrhosis  of  liver,  alcohol  and,  308,  309 
Citrate  of  iron  and  quinine,  500 
and  strychnine,  500 
dose,  254 
of  magnesia,  dose,  129 
Citrated  caffeine,  239 
dose,  239 

effervescent,  dose,  239 
Citrates,  85 
Citric  acid,  83,  85 

effect  of,  on  clotting  of  blood,  83 
in  typhoid  fever,  83 
Citrine  ointment  as  antiseptic,  485 
Citrophen,  436 
Clark's  rule  for  dosage,  48 
Clay  poultice,  71 
Clitocybe  illudens,  418 
Clotting  of  blood,  effect  of  calcium  on, 

93 
of  citric  acid  on,  83 
of  milk  by  rennet,  calcium  in,  93 
Coagulation  of  blood,  effect  of  calcium 
on,  93 
of  citric  acid  on,  83 
Coal-gas,  poisoning  from,  532 
Coca,  387 

constituents,  387 
fluidextract,  dose,  387 
preparations  and  doses,  387 
wine,  dose,  387 
Cocaine,  387 
chloride,  387 

as  anesthetic,  395 
dose,  387 

excretion,  393 
habit,  394 

treatment,  395 
hydrochloride,  387 
in  diseases  of  anus,  396 
of  esophagus,  396 
of  nose,  395 
of  stomach,  396 
of  throat,  395 
in  spasm  of  urethra,  396 


INDEX 


573 


Cocaine  in  itching  of  vulva,  396 
in  vaginismus,  396 
intravenous  anesthesia  with,  397 
oleate,  387 

pharmacologic  action,  388-394 
poisoning,  394 

spinal  anesthesia  with,  389,  390,  396 
substitutes,  397 
therapeutics,  395 
toxicology,  394 
untoward  effects,  393 
Cocktail,  302 
Cocoa,  31,  253 

nibs,  252 
Cocoa-butter,  30,  253 
Cocoanut  oil,  30 
Codeine,  352,  353,  366 
dose,  353 
in  cough, 366 
in  diabetes,  365 
phosphate,  353 
sulphate,  353 
Cod-liver  oil,  30,  66 

preparations  and  doses,  67 
Coffee,  239,  249 
habit,  251 

pharmacologic  action,  251 
tolerance,  252 
Cognac,  301 
Colchicine,  dose,  458 
Colchicum,  457 

pharmacologic  action,  458 
poisoning  from,  458 
preparations  and  doses,  458 
Cold,  71,  434 

air  as  circulatory  stimulant,  147 
as  preservative,  462 
bath,  344 
Cold-pack,  435 
Colds,  camphor  in,  203 
Colic,  camphor  in,  203 
chloroform  in,  275 
lead,  490 
painter's,  490 
Colitis,  amebic,  emetine  chloride  in,  524 
ipecac  in,  524 
quinine  in,  449 
Collapse,  233 
caffeine  in,  247 
camphor  in,  203 
carbon  dioxide  in,  237 
cause,  Crile's  theory,  234 

Henderson's  theory,  234 
counterirritants  in,  73 
epinephrine  in,  236 
in  anesthesia,  treatment,  294 
in    chloroform    anesthesia,  amyl  ni- 
trite in,  231 
treatment,  294 
in  ether  anesthesia,  280 
treatment,  294 


Collapse,  mechanical  measures  in,  210 
pituitrin  in,  236 
respiratory  paralysis  and,  235 
saline  infusion  in,  216 
symptoms,  235,  236 
transfusion  of  blood  in,  212,  237 
treatment,  235,  236 
Collargol,  497 
Collodion,  definition,  41 
Colloid  goiter,  iodides  in,  519 

thyroid  gland  in,  522 
Colloidal  silver,  497 
Colocynth,  compound  extract  of,  128 

poisoning  from,  126 
Cologne  spirit,  298 
Colon  as  factor  in  defecation,  112 

irrigations  of  saline  solution,  135 
Colon-bacillus  infection  of  urinary  tract, 

Burow's  solution  in,  498 
Colonic  anesthesia,  291 
Colors  for  prescription,  540 
Coma,  266 

Compensation  of  heart,  146 
Compound  acetanilid  powder,  239,  436 
cathartic  pills,  128 
cresol  solution,  470 
extract  of  colocynth,  dose,  127 
jalap  powder,  1 28 
laxative  pills,  dose,  254 
licorice  mixture,  523 

powder,  124 
morphine  powder,  353  _ 
pharmaceutic  preparations,  40 
rhubarb  pills,  123,  124 

powder,  124 
solution  of  iodine,  515 
spirit  of  juniper,  301 

of  orange,  302 
syrup  of  hypophosphites,  500 
dose,  254 
of  sarsaparilla,  124 
of  squill,  151,  S12 
as  expectorant,  523 
tincture  of  cinchona,  101 
dose,  444 
of  gentian,  101 
of  lavender,  100 
Compressed  tablets,  541 

definition,  42 
Confectio,  definition,  42 
Congestion,  counterirritants  for,  73 
Conium,  404 
Conjunctions,  Latin,  545 
Conjunctival  argyria,  498 
Conjunctivitis   after   ether   anesthesia, 
281 
copper  sulphate  in,  493 
zinc  sulphate  in,  493 
Connective-tissue  changes  in  heart  and 

arteries  from  epinephrine,  191 
Constipation,  no 


574 


INDEX 


Constipation,  chronic,  hormonal  in,  80 

etiology,  in 

from  deficient  motility,  in 

from  insufficiency  of  normal  stimuli, 
in 

from  lack  of  sensitiveness  to  stimuli, 
in 

from  organic  obstruction,  in 

from  spasmodic  obstruction,  in 

habitual,   anthracene  derivatives  in, 
123 

saline  cathartics  in,  objections,  133 
Continuous  drop  irrigation,  135 
Contraindication,  62,  63 
Convalescence,  alcohol  in,  334 
Convallamarin,  150 
Convallaria,  150 
Convallarin,  150 
Convulsions,  bromides  in,  350 
Convulsive  reflexes,  259 
Coordinated  reflexes,  257 
Copper,  492 

as  antiseptic  and  disinfectant,  466 

poisoning,  493 

therapeutics,  493 
Copperas  as  disinfectant,  499 
Cordials,  301 
Corn  whisky,  300 
Corn-starch,  28 
Corns,  salicylic  acid  for,  455 
Coronary    arteries,    constriction,    from 
digitalis,  167 

circulation,  142 

adequate,  maintenance  of,  145 
Corrosive  sublimate  as  disinfectant,  484 
Cotarnine  chloride,  531 
Cottonseed  oil,  30 
Cough,  codeine  in,  366 

dionine  in,  367 

heroine  in,  367 

lactucarium  in,  369 

morphine  in,  357 

strychnine  in,  261 
Counterirritants,  67 

as  antemetics,  104 

cautions,  73 

mode  of  action,  68 

preparations,  70 

therapeutics  of,  73 
Counterirritation,  67 
Cowling's  rule  for  dosage,  49,  549 
Coxe's  hive  syrup,  512 

as  expectorant,  523 
Cramp  from  cathartics,  113 
Cream  of  tartar,  94,  95 

dose,  129 
Crede's  method  of  prophylaxis  against 

gonorrheal  ophthalmia,  496 
Creme  de  menthe,  302 
Cremes,  301 
Creolin,  470 


Creosote,  36,  469 

carbonate,  469 
Cresol,  470 

compounds,  465 

solution,  compound,  470 
Creta  praeparata,  91 
Cretinism,  thyroid  gland  in,  521 
Crile's  pneumatic  suit  in  shock,  211,  237 

theory  as  to  cause  of  shock  and  col- 
lapse, 234 
Croton  oil,  31,  127 

dose,  127 
Crotonic  acid,  127 
Croup,  mercury  subsulphate  in,  486 
Croupous  laryngitis,  calomel  in,  486 
Crude  drugs,  19 
Crystalline  gratus  strophanthin,  151 

elimination,  173 
Cumulative  poison,  47 
Cupping,  dry-,  71,  232 

wet-,  232 
Cuprum,  492 
Curare,  404 

Cusso  for  tape-worms,  no 
Cutaneous  arteries,  action  of  digitalis 
on  circulation  through,  170 

arterioles,  caliber,  144 
Cyanides,  402 

pharmacologic  action,  403 

poisoning  from,  403 

preparations,  402 
Cyanosis  in  anesthesia,  treatment,  293 

oxygen  in,  534 
Cycloplegic,  definition,  379 
Cystogen,  478 


Dating  prescription,  536 
Datura  stramonium,  370 
Dawson's  solution  for  saline  infusion, 

213 
Deadly  agaric,  418 
nightshade,  370 
Deafness  from  smoking,  411 
Death's-head  fungus,  418 
Debility,  alcohol  in,  334 
Decoction,  definition,  40 
Decoctum,  definition,  40 
Defecate,    lesponse    to    desire    to,    as 

cathartic  measure,  114 
Defecation,  mechanical  factors  of.  in 
cecum  and  colon,  112 
small  intestines,  in 
Degeneration,  fatty,  of  heart,  digitalis 

in,  '182 
Delayed  chloroform  poisoning,  286 
Delirium  tremens,  329 
ergot  in,  329,  529 
hyoscine  in,  385 
treatment,  329 
Delphinium,  221 


INDEX 


575 


Demulcents,  65 
Denatured  alcohol,  298 
Deodorant,  459 
Deodorized  alcohol,  298 

opium,  352 
Deodorizer,  459 
Deodorizers  used  as  gas,  481 
in  dry  form,  481 
in  solution,  481 
Deoxidizers,  464 
Depressants,  cardiac,  217 
Depression,  56 

Desiccated  thyroid  glands,  519 
Dextrin,  29 
Dextrose,  28 

diuretic  action,  429 
Diabetes,  antipyrine  in,  443 

codeine  in,  365 

ergot  in,  529 

morphin  in,  365 

opium  in,  365 

salicylic  acid  in,  455 
Di-acetyl  morphine,  366 
Diacetyl-phenolphthalein,  125 
Diacetyltannin,  107 
Diamino-dihydroxy-arsenobenzol        di- 

hydrochloride,  505 
Diaphoresis,  419 

character  of  sweat  in,  422 

fat  and,  422 

in  chronic  rheumatism,  424 

in  nephritis,  423,  424 

in  sickness,  423 

in  uremia,  423 

measures  to  produce,  419 

relation  of,  to  nitrogenous  excretion, 
422 
Diaphoretics,  419 

administration,  424 

therapeutics,  424 

to  assist  kidneys,  424 

to  hasten  outbreak  of  rash,  424 

to  lessen  congestion  of  internal  eye, 
424 
edema  and  promote  absorption  of 

dropsical  effusions,  424 
obesity,  424 

to  lower  temperature,  424 

to  overcome  chill  or  coid,  424 
Diarrhea,  remedies  for,  136 
Diaspirin,  456 
Diastase,  79 
Dietetic  measures,  18 
Di-ethyl  barbituric  acid,  344 

malonyl  urea,  344 

morphine  chloride,  399 
Diethylene-diamine,  458 
Diffusion,  213 
Digalen,  149 
Digestive  ferments,  76 
Digipuratum,  149 


Digitalein,  148 
Digitalin,  148 

dose,  149 
Digitalis,  148 

absorption  of,  154 
allies,  150 

elimination,  173 
arhythmia  from,  156 
auricular  fibrillation  from,  159 
bradycardia  from,  156 
complete  heart-block  from,  163,  164 
constituents,  148 
constriction     of     coronary     arteries 

from,  167 
coupled  rhythm  of  heart  from,  166 
diuresis,  171 
dose,  148 

elimination  of,  173 
extract  of,  dose,  148 
fluidextract  of,  dose,  148,  149 

objections,  149 
group, 150 

heart-block  from,  162,  163 
in  aneurysm  of  aorta,  185 
in  aortic  insufficiency,  183 

stenosis,  184 
in  aortitis,  185 
in  arteriosclerosis,  185 
in  auricular  fibrillation,  179 

flutter,  181 
in  chronic  myocarditis,  182 
in  dilatation  of  heart,  182 
in  dropsy,  171,  172 
in  edema,  171,  172 
in  failure  of  compensation  of  heart, 

184 
in  heart-block,  179 
in  high  arterial  pressure,  181 
in  infectious  diseases,  185 
in  mitral  insufficiency,  183 

stenosis,  184 
in  muscular  inability  of  heart  with 
valvular  lesion,  182 
without  valvular  lesion,  182 
in  paroxysmal  tachycardia,  179 
in  pneumonia,  185 
in  premature  contractions  of  heart, 

179 
in  pulsus  alternans,  1 79 
in  sinus  arhythmia,  179 
in   threatened   failure   of   compensa- 
tion of  heart,  184 
in  toxic  myocarditis,  182 
in  venous  engorgement,  171 
in  water-retention,  172 
incipient  heart-block  from,  162 
indications,  185 

influence  of  conditions  of  arteries  on 
usefulness,  182 
of  heart  on  usefulness,  182 
infusion  of,  dose,  148,  149 


576 


INDEX 


Digitalis,  irritability  of  heart  from,  158 
nodal  rhythm  of  heart  from,  161 
overirritability  of  heart  from,  158 
paroxysmal  tachycardia  from,  161 
partial  heart-block  from,  162 
permanency  of  preparations,  151 
pharmacologic  action,  153-174 
phasic  arhythmia  from,  166 
poisoning  from,  174 

cumulative,  176 

overwhelming  dose,  174 

single  large  dose  by  mouth,  175 

symptoms,  176,  177 

treatment,  178 
premature  heart-beats  from,  159 
preparations  and  doses,  148 

standardization   and   permanency, 

151 

pulsus  alternans  from,  167 

purpurea,  148 

retention  of  urine  from,  171 

reversed  rhythm  of  heart  from,  161 

series,  150 

slowing  of  heart  from,  156 

standardization  and  permanency  of 
preparations,  151 

suppression  of  urine  from,  171 

therapeutics,  178 
summary,  185 

tincture  of,  dose,  148,  149 

toxicology,  174 

use  as   determined  by   rhythm  and 
rate  of  heart,  181 

value  of,  172 

ventricular  fibrillation  from,  161 
Digitalosmin,  148 
Digitonin,  20,  148 
Digitoxin,  148 

dose,  149 
Dilatation  of  heart,  146 

digitalis  in,  182 
Dilators,  arterial,  225 
Dilute  nitric  acid,  therapeutics,  83 

nitrohydrochloric  acid,  81 
therapeutics,  83 

phosphoric  acid,  therapeutics,  83 
Diluted  acetic  acid,  84 

alcohol,  298 

hydriodic  acid,  515 

hydrocyanic  acid,  402 
Dimethyl-amidophenyl-dimethyl       py- 

razolon,  436 
Di-methyl-amino-benzoyl  pentanol  chlo- 
ride, 397 
Dimethyl-ethyl  carbinol,  346 
Dionine,  367,  369 

in  cough,  367 
Diplosal,  456 
Dipropaesin,  399 
Dipsomania,  327 
Direct  local  action,  52 


Disease,  nature  of,  dose  and,  51 
Disinfectants,  459 
bladder,  483 
bronchi,  483 
classification,  462 
therapeutic,  481 
eye,  483 

for  dressings,  482 
for  local  use  about  body,  482 
for  obstetrician's  hands,  482 
for  skin,  482 
for  surgeon's  hands,  482 
for  surgical  instruments,  482 

supplies,  482 
in  skin  diseases,  483 
intestinal,  483 
larynx,  483 
mouth,  483 
nose,  483 
open  wounds,  483 
rectum,  483 
respiratory,  483 
stomach,  483 
tests  for  value,  460 
therapeutic  classification,  481 
throat,  483 

to  be  given  by  mouth,  483 
urethra,  483 
urinary  tract,  483 
used  as  gas,  481 
in  dry  form,  4 
in  solution,  481 
Dispensatory,  47 
Distention   of   stomach  and  intestines 

after  ether  anesthesia,  281 
Distilled  liquors,  300 

from    fermented    saccharine   fruit- 
juices,  301 
from  malt  liquors,  301 
medicinal  dose,  303 
Diuresis,  425 

caffeine,  244,  246 
digitalis,  171 

in  acute  nephritis,  433,  434 
in  chrcnic  nephritis,  434 
production  of,  427 
by  calomel,  430 
by  dextrose,  429 
by   increasing   blood-flow   through 

kidney,  428 
by  inorganic  salts,  429 
by   lowering  osmotic   pressure  of 

blood,  428 
by  measures  which  decrease  tubular 
absorption,  430 
which  increase  glomerular  fluid, 
428 
tubular  secretion,  430 
by  organic  salts,  429 
by  urea,  429 
by  water,  429 


INDEX 


577 


Diuresis,  secretion  threshold  in,  431 

therapeutics,  433 

to  cause  removal  of  dropsy  and 
edema,  433 

to  promote  elimination  of  poisons,  433 
Diuretics,  425 

therapeutics,  431 

to  cause  removal  of  dropsy  and 
edema,  433 

to  promote    elimination  of   poisons, 

433 
Diuretin,  249 
Dobell's  solution,  471 
Dog-bites,  caustics  for,  74 
Donovan's  solution,  504 
Dormiol,  346 
Dosage,  47 

Clark's  rule,  48 

Cowling's  rule  for,  49,  549 

for  children,  Bastedo's  rule,  548 
Cowling's  rule,  549 

Fried's  rule  for,  49 

Young's  rule  for,  49 
Dose,  47 

age  and,  48 

body  weight  and,  48 

channel  of  administration  and,  51 

factors  which  modify,  48 

for  children,  48 

form  of  remedy  and,  51 

frequency  of  administration  and,  52 

idiosyncrasy  and,  50 

maximum,  47 

minimum,  47 

nature  of  disease  and,  51 

object  of  medication  and,  51 

occupation  and,  50 

previous  habits  and,  50 

race  and,  50 

repeated,  47 

sex  and,  50 

single,  47_  _ 

susceptibility  and,  50 

temperature  and,  50 

therapeutic,  47 

time  of  administration  and,  52 

toleration  and,  50 

toxic,  47 
Dover's  powder,  dose,  352 
Drastics,  125 

cautions,  127 

doses,  127 

pharmacologic  action,  125 

poisoning  from,  126 
treatment,  126 

preparations,  127 

therapeutics,  127 

uses,  125 
Dressings,  disinfectants  for,  482 
Drink,  Imperial,  83 
Drip  sheet,  435 

37 


Drop    method    of    administration    of 
chloroform,  289 
of  ether,  289 
Drop-chalk,  91 
Drops,  538 
Dropsy,  caffeine  in,  248 

digitalis  in,  171,  172 
Drugs,  active  constituents,  19.  20 

administration     of,     52.     See     also 
Administration 

as  cathartic  measures,  1 16 

assayed,  45 

crude,  19 

effect  of,  on  cells,  56 

how  much  to  learn  about,  61 

irritants,  time  to  give,  55 

organic,  constituents  of,  19 
constituents  of,  active,  19,  20 

selective,  56 

sites  and  modes  of  action,  56 

varieties,  19 
Drunkenness,  325 

after-effects,  326 

treatment,  326 
Dry  wane,  300 
Dry-cupping,  71,  232 
Dwarf  tape-worms,  remedies  for,  no 
Dysentery,  amebic,  emetine  chloride  in, 

524 
ipecac  in,  524 
Dyspnea,  Hoffmann's  anodyne  in,  267 


Early-bird    mixture,   poisoning   from, 

no 
Eau  de  Javelle,  464 
Eclampsia,  veratrum  in,  224 
Edema,  digitalis  in,  171,  172 
Effervescent  citrated  caffeine,  239 

salt,  granular,  definition,  42 
Effervescing  magnesium  sulphate,  dose, 
129 

mineral  waters,  137 

potassium  citrate,  dose.  129 

sodium  phosphate,  dose,  1 29 
Effusion,  pleural,  calcium  chloride  in.  93 
Egg-albumin  tannate,  107 
Egg-nog,  302 
Ehrlich's  "606,"  505 
Elaterin,  26,  127 

dose,  127 
Electric  bath,  420 
Eleopten,  35 
Elixir  adjuvans,  99,  302 

aromatic,  99 

aromaticum.  302 

definition,  41 

of  phosphates  of  iron,  quinine,  and 
strychnine,  302,  500 
dose,  254 
Elixirs,  301 


578 


INDEX 


Elixirs,  pharmaceutic,  301 
Elm,  slippery,  29 
Emetics,  102 

central,  103 

reflex,  103 

therapeutics,  103 
Emetine,  523 

chloride,  dose,  524 

in  amebic  dysentery,  524 
Emmenagogues,  525 
Emodin,  122 
Emollients,  65 
Empiric  therapeutics,  58 
Emplastrum,  definition,  42 
Empyreumatic  oils,  34 
Emulsin,  25,  27 
Emulsion,  artificial,  41 

definition,  41 
Emulsions,  natural,  41 
Emulsum,  definition,  41 
Encephalopathy,  lead,  491 
Endurance,  effect  of  caffeine  on,  241 
Enema,  55,  134 

cathartic,  134 

as  softening  agent,  134 

evacuating,  134 

nutritive,  135 

of  salt  solution,  216 

to  induce  expulsion  of  gas,  135 
Enteric  pills,  37,  524,  540 
Entoloma  sinuatum,  418 
Enzymes,  27 

Epilepsy,  bromipin  in,  351 
Epinephrine,  186 

absorption  of,  188 

and    chloroform,    simultaneous    use, 
effects,  194 

chloride,  solution  of,  187 
dose,  187 

connective-tissue    changes    in    heart 
from,  191 

dangers,  196 

elimination  of,  193 

hypodermic  injection,  195 

in  Addison's  disease,  195 

in  anterior  poliomyelitis,  195 

in  bronchial  asthma,  195 

in  collapse,  236 

in  epistaxis,  195 

in  hemorrhage,  195 
from  nose,  195 

in  internal  hemorrhage,  191 

in  itching  of  vulva,  195 

in  nose-bleed,  195 

in  postpartum  hemorrhage,  195 

in  shock,  236 

intramuscular  injection,  effects,  189 

intravenous  administration,  195 
dangers,  196 
effects,  189 

local  effects,  194 


Epinephrine,  pharmacologic  action,  187- 

193  . 
poisoning  from,  194 
preparations  and  doses,  187 
slowing  of  heart  from,  190 
subcutaneous  injection,  effects,  188 
therapeutics,  194 
to  prolong  anesthesia,  195 
tolerance,  193 
toxicology,  194 
Epispastic,  68 
Epispastics,  72 

Epistaxis,  epinephrine  in,  195 
Epsom  salt,  400 

as  anesthetic,  400,  401 
dose,  129 
in  pain,  402 
in  shock,  401 
in  tetanus,  401 
therapeutics,  401 
Equinine,  444 
Ergot,  525 

constituents,  525 
deterioration,  526 
dose,  526 
extract,  dose,  526 
lluidextract,  dose,  526 
in  delirium  tremens,  329,  529 
in  diabetes,  529 
in  menorrhagia,  529 
in  subinvolution  of  uterus,  529 
pharmacologic  action,  527,  528 
poisoning,  528 
chronic,  529 
preparations  and  doses,  526 
standardization,  526 
therapeutics,  529 
to  prevent  postpartum  hemorrhage, 

529 

toxicology,  528 

wine,  dose,  526 
Ergota,  525 
Ergotine,  525 
Ergotism,  529 

gangrene  in,  529 

nervous  type,  529 
Ergotoxine,  525 

phosphate,  dose,  526 
Eriodictyon,  101,  400 
Erythrol  tetranitrate,  225 

effect,  228 
Erythroxylon  coca,  387 

truxillense,  387 
Escharotics,  73 

therapeutics,  74 

toxicology',  74 
Eseridine,  411 
Eserine,  411 

Esophagus,  diseases  of,  cocaine  in,  396 
Essences  of  plants,  34 
Essential  oils,  34 


INDEX 


579 


Ether,  267 

absorption,  267 
administration,  288 
anesthesia,  277 

administration    of    sodium    bicar- 
bonate, 283 
after-effects,  280 
albuminuria  after,  274 
amount  necessary  to  produce,  290 
closed   inhalers  for  administering, 

289 
collapse  in,  280 

saline  infusion  in,  294 
treatment,  294 
conjunctivitis  after,  281 
danger-signs,  280 
diluting  with  oxygen,  282 
distention  of  stomach  and  intestines 

after,  281 
drop  method  of  administration,  289 
feeding    with    carbohydrates    and 

water,  282 
first  stage,  278 
fourth  stage,  279 
having  stomach  empty,  282 
helpful  measures  in,  282 
indications,  283 
injection  of  atropine  sulphate  in, 

281 
intravenous,  292 
kidneys  after,  281 
nausea  after,  280 

open-cone   method   of   administra- 
tion, 289 
pain  in  back  after,  281 
post-operative  gastric  or  intestinal 

paralysis  after,  281 
preliminary  administration  of  seda- 
tive drugs,  282 
anesthetization  with  chloroform, 
282 
with  ethyl  chloride,  28 2 
with  nitrous  oxide,  282 
preventive  measures  in,  282 
reassuring  patient,  282 
recovery  from,  280 
respiratory  troubles  after,  281 
second  stage,  278 
sore  tongue  after,  281 
third  stage,  279 
thirst  after,  281 
untoward  sequels,  281 
vomiting  after,  280 
warming  vapor,  282 
compound  spirit,  dose,  267 
dose,  267 
elimination,  270 
habit,  270 
inhalations  in   strychnine  poisoning, 

263 
nitrous,  spirit  of,  226 


Ether,  poisoning  from,  269 

preparations  and  doses,  267 

rash,  270 

therapeutics,  270 

toxicology,  269 
Ethyl  alcohol,  297 

bromide  anesthesia,  297 

chloride,  267,  296 
anesthesia,  297 
local  action,  296 
preliminary    anesthetization    with, 

in  ether  anesthesia,  282 
spray,  399 

ester  of  para-amido-benzoic  acid,  399 
Ethylated  compounds,  343 
Ethyl-morphine  chloride,  367 
Eucaine,  397 
Eucalyptol,  99 

as  antiseptic,  470 
Eugenol,  99,  470 
Euonymus,  127 

dose,  127 

extract  of,  dose,  127 
Euphthalmine,  386 
Europhen,  466 
Evacuating  enema,  134 
Exalgine,  436 
Excipient,  540 

Exercise  as  cathartic  measure,  114 
Exophthalmic  goiter,  atropine  in,  383 
Expectant  treatment,  60 
Expectorants,  522 
Experimentation,  animal,  58 
Extract,  definition,  41 
Extraction,  38 
Extractive,  38 
Extractum,  definition,  41 

malti,  67 
Eye,  diseases  of,  atropine  in,  382,  383 

disinfectants,  483 


Falk  and  Tedesco's  salicylic  test,  453 
False  anesthesia,  280 
Fat  allies,  32 

sweating  and,  422 
Fats,  30 

animal,  30 

vegetable,  30 
Fatty  degeneration  of  heart,   digitalis 

in,  182 
Feces,    impacted,    cathartic   enema   to 

soften,  134 
Feet,  sweating  of,  salicylic  acid  in,  455 
Ferments,  27 

digestive,  76 
Ferratin,  501 
Ferri  hydroxidum,  499 

cum  magnesii  oxido,  499 
Ferric  acetate,  500 


58o 


INDEX 


Ferric  citrate,  500 

hydroxide,  499 

salts,  inorganic,  500 

tartrate,  500 
Ferrous  salts,  inorganic,  500 

sulphate,  464 

as  disinfectant,  499 
Ferruginous  waters,  137 
Ferrum,  499 

reductum,  500 
Fever,  aconite  in,  221 

alcohol  in,  334 

camphor  in,  203 

iodide,  518 

reduction  of,  remedies,  434 
Fibrillation,     auricular,      digitalis      in, 
179 
from  digitalis,  159 

ventricular,  from  digitalis,  161 
Fibrolysin,  75 

therapeutics,  75 
Field  mushroom,  419 
Filicic  acid,  amorphous,  for  tape-worms, 

no 
Filtration,  213 
Fixed  oils,  30 

as  cathartics,  11S 
Flatulence,  camphor  in,  203 

chloroform  in,  275 
Flavors  for  prescription,  539 
Flaxseed,    whole,    to   increase   bulk   of 

feces,  116 
Flowers  of  sulphur  as  laxative,  117 
Fluidextract,  definition,  41 
Fluidextractum,  definition,  41 
Flutter,  auricular,  digitalis  in,  1S1 
Fly  agaric,  417,  418 

Spanish,  72 
Fly-blister,  72 
Food  as  cathartic  measure,  114 

iron,  501 

passage  of,  from  stomach  to  rectum, 
time  required,  112 

preservatives,  481 

value  of  alcohol,  313-319 
Foot-bath,  mustard,  72 
Formaldehvd,  476 

poisoning  from,  477 
treatment,  47S 

therapeutics,  477 
Formaldehyd-tannin,  107 
Formalin,  476 

Formanganate  disinfector,  477 
Formic  acid,  84 

in  rheumatism,  84 
Formin,  478 

Formulary,  National,  46 
Fortified  wines,  300 
Fossy  jaw.  514 
Fowler's  solution,  504 
Foxglove,  148 


Fractures,  delayed  union,  thyroid  gland 

in,  522 
Frangula,  124 
Fraxinus  ornus,  2S 
French  brandy,  301 
Fried's  rule  for  dosage,  49 
Fruit  acids,  85 

Fruits  as  cathartic  measure.  115 
Fungi,  poisonous,  418 
Fungus,  death's-head,  418 
Furfurol,  406 


Gamboge,  dose,  127 
Ganglia,  vagus,  141 
Gangrene  in  ergotism,  529 
Ganja,  368 
Gas,  coal-poisoning  from,  532 

expulsion  of,  enema  for,  135 

illuminating-,  poisoning  from,  532 
Gasoline,  33 
Gastric  irritation,  bismuth  in,  495 

juice,  appetite,  100 
psychic,  100,  306 

paralysis,  post-operative,  after  ether 
anesthesia,  281 

ulcer,  scarlet  R  in,  75 
Gastritis,  chronic,  silver  nitrate  in,  496 
Gauze,  balsam,  469 
Gelatin,  37 

glycerinated,  37 

in  aneurysm,  37 

in  hemorrhage,  37 
Gelatinum,  37 
Gelseminine,  404 
Gelsemium,  404 

in  trifacial  neuralgia,  404 
General  protoplasm  poisons,  56 
Genital  organs,  action  of  carminatives 

on,  96 
Genito-urinary  organs,  action  of  cam- 
phor on,  202 
Gentian,  compound  tincture  of,  101 
Germicides,  459 
Gin,  301 

Glacial  acetic  acid,  84 
Gland,  suprarenal,  dried,  dose  of,  187 

thyroid,  519 
Glandulae  suprarenales  siccae,  187 

thyroidese  siccae,  519 
Glassfuls,  539 
Glauber's  salt,  dose,  129 
Glomerulus  of  kidney,  functions,  426 
Glonoin,  225 

spirit  of,  225 
Glucose,  24,  25,  28 

in  shock,  28 
Glucosides,  24 
Glutol  capsules,  476 
Glycerin,  30.  31 

as  cathartic,  118 


INDEX 


58l 


Glycerin  suppositories,  31,  136 
Glycerinated  gelatin,  37 
Glycerinum,  31 
Glycerite,  definition,  41 

of  boroglycerin,  467 

of  phosphates  of  iron,  quinine,  and 
strychnine,  dose,  254 
Glycerites,  31 
Glyceritum,  definition,  41 
Glycerophosphates,  514 
Glyceryl,  30 

trinitrate,  225 
Gly co-heroin,  367 
Glycosides,  24 
Glycyrrhizin,  21 
Goiter,  colloid,  iodides  in,  519 
thyroid  gland  in,  522 

exophthalmic,  atropine  in,  383 
Gold  as  antiseptic  and  disinfectant,  466 
Goldenseal,  530 
Gonorrheal  ophthalmia,  Crede's  method 

of  prophylaxis  against,  496 
Goulard's  extract,  489 
Gout,  alcohol  in,  324 

atophan  in,  458 

cimicifuga  in,  458 

colchicum  in,  458 

lithium  in,  87 

salicylic  acid  in,  455 
Grain  alcohol,  297 
Granatum  for  tape-worms,  no 

poisoning  from,  no 
Granular  effervescent  salt,  definition,  42 
Granulated  opium,  352 
Green  soap,  32 
tincture  of,  32 

tea,  250 
Griping  from  cathartics,  113 
Guaiacol,  470 

carbonate,  470 
Guanin,  238 
Guarana,  239 
Gum  arabic,  29 

British,  29 

cherry-,  29 

resin,  36,  41 
Gums,  27,  29 
Gymnemic  acid,  101 


Habit,  alcohol,  cure  of,  329 
chloroform,  275 
cocaine,  394 

treatment,  395 
coffee,  251 
ether,  270 

formation  as  cathartic  measure,  113 
hasheesh,  368 
heroine,  367 
kola,  252 
morphine,  362 


Habit,  paraldehyd,  346 
tea,  251 
tobacco,  408 
Habits,  previous,  dose  and,  50 
Habitual    constipation,    anthracene 

derivatives  in,  123 
Halogens,  free,  464 

compounds,  464 
Hands,  obstetrician's  disinfectants  for, 
482 
surgeon's,  disinfectants  for,  482 
sweating  of,  salicylic  acid  in,  455 
Hard  soap,  31 
Harrington's  solution,  485 
Hasheesh  habit,  368 
Hashish,  368 

Headache,  quinine  in,  450 
Head's  areas,  69 

Heart,  action  of,   influences  affecting, 
140 
remedies  affecting,  directly,  140 
indirectly,  140 
blood   in,   output   of,   influences   af- 
fecting, 139 
blood-supply,  144 
compensation,  146 
failure  of,  146,  147 
digitalis  in,  184 
threatened  failure,  147 
digitalis  in,  184 
conditions    of,     influence,     on    use- 
fulness of  digitalis,  182 
connective-tissue    changes    in,    from 

epinephrine,  191 
contractility,  142 

action  of  digitalis  on,  157 
contractions,  premature,  digitalis  in, 

179 
dilatation  of,  146 
digitalis  in,  182 
fatty  degeneration,  digitalis  in,   182 
increased  force,  from  epinephrine,  190 
irritability  of,  from  digitalis,  158 
muscle,    action    of    digitalis    on    cir- 
culation through, 157 
muscular    inability,     with    valvular 
lesion,  digitalis  in,  182 
without    valvular    lesion,    digi- 
talis in,  182 
normal  rhythm,  digitalis  in,  181 
nutrition  of,  action  of  digitalis  on,  167 
optimum  rate,  142 

overirritability  of,  from  digitalis,  158 
premature  contractions,  digitalis  in, 

179 
rate,  142 

recuperative   power,   action  of  digi- 
talis on,  167 
resistance,  142 
rest  force,  147 
rhythm  of,  coupled,  from  digitalis,  166 


582 


INDEX 


Heart  rhythm,  influences  affecting,  142 

nodal,  from  digitalis,  161 

normal,  156 

reversed,  from  digitalis,  161 
right    ventricle,    action    of    digitalis 

on,  158 
slowing  of,  from  digitalis,  156 

from  epinephrine,  190 
tobacco,  411 
tone,  142 

tonicity  of,  action  of  digitalis  on,  157 
working  force,  147 
Heart-beats,  premature,  from  digitalis, 

159 
Heart-block,  complete,    from    digitalis, 
163,  164 

digitalis  in,  179 

from  digitalis,  162,  163 

incipient,  from  digitalis,  162 

partial,  from  digitalis,  162 
Heat,  70 

as  disinfectant,  462 

body-,  methods  of  raising,  419 
Heat-regulating  center,  action  of  aco- 
nite on,  219 
Heavy  metals,  483 

oxide  of  magnesium,  90 

wine,  300 
Hedonal,  345 
Hellebore,  American,  222 

white,  222 
Helleborein,  muscular  effects,  174 
Hematinics,  iron,  499,  500 
Hemlock,  poison,  404 
Hemorrhage,  calcium  in,  93 

epinephrine  in,  195 

gelatin  in,  37 

internal,  epinephrine  in,  191 

mechanical  measures  in,  210 

nasal,  antipyrine  in,  443 
epinephrine  in,  195 

postpartum,  epinephrine  in,  195 
prevention,  ergot  in,  529 

pulmonary,  pituitary  extract  in,  198 

saline  infusion  in,  216 

transfusion  of  blood  in,  212 
Henbane,  370 

Henderson's    theory    as    to    cause    of 
collapse,  234 
of  shock,  234 
Heroine,  366 

habit,  367 

in  cough,  367 
Hexamethylenamine,  24,  478 

administration,  480 

therapeutics,  480 

untoward  effects,  480 
Hexamethylenamine-tannin,  107 
Highball,  302 
Hirudin,  233 
Hirudo,  232 


Hoffmann's  anodyne,  dose,  267 
in  angina  pectoris,  271 
in  dyspnea,  271 
in  hysteria,  271 
in  spasm,  271 
therapeutic  uses,  271 
Hog-back  kidney,  331 
Holocaine,  399 
Homatropine,  24 

bromide,  385 
Honey,  definition,  41 
Hookworms,  treatment,  109 
Hops,  369 
Hormonal,  80 

in  chronic  constipation,  80 
Horrors,  329 
Hot-air  bath,  420 
Hot-pack,  420 
Humulus,  369 

in  pain,  369 

lupulus,  369 
Hydragogue,  113 

Hydrargyri    chloridum    corrosivum    as 
disinfectant,  484 
mite,  120 
Hydrargyrum,  484 
Hydrastine,  530 

dose,  530 

elimination,  531 
Hydrastininae  chloridum,  531 
Hydrastinine,  24 

chloride,  531 

therapeutics,  531 
Hydrastis,  106,  530 

canadensis,  530 

constituents,  530 

dose,  530 

fluidextract,  dose,  530 

glycerite,  dose,  530 

pharmacologic  action,  530,  531 

preparations,  530 

therapeutics,  531 

tincture,  dose,  530 
Hydrated  chloral,  338 
Hydremic  plethora,  428 
Hydriodic  acid,  diluted,  515 
Hydrochloric  acid,  81 
therapeutics,  82 
Hydrocyanic  acid,  402 
diluted,  402 
preparations,  402 
therapeutics,  403 
Hydrotherapeutic  measures,  18 
Hygienic  measures,  17 
Hyoscine,  384 

as  anaphrodisiac,  385 

as  general  anesthetic,  385 

as  mydriatic  and  cycloplegic,  385 

as  narcotic,  385 

bromide,  372 

in  delirium  tremens,  385 


INDEX 


583 


Hyoscine  in  insomnia,  385 

therapeutics,  385 
Hyoscyamine,  371,  384 

bromide,  371 

sulphate,  371 
Hyoscyamus,  370,  371 

dose,  372 

niger,  370 

therapeutics,  384 
Hyperchlorhydria,  silver  nitrate  in,  490 
Hyperthyroidism,  atropine  in,  383 

iodides  in,  519 

pancreatin  in,  77 
Hypertonic  solutions,  213 
Hypnotic  measures,  336,  337 
Hypnotics,  335  ^ 

ethylated,  344 
to  abolish  pain,  347 
which  do  not  diminish  pain,  338 
Hypochlorites,  464 
Hypodermatic  administration,  52 
advantages,  54 
disadvantages,  54 
Hypodermatoclysis,  administration  by, 

Hypodermic   injection   of   epinephrine, 

195 

tablets,  53-  54*        ,.        ...        , 
Hypodermoclysis,    saline    infusion    by, 

Hypophosphites,   compound  syrup   of, 
dose,  254 
of  phosphorus,  514 
Hypothyroidism,  thyroid  gland  in,  521 
Hypotonic  solutions,  213 
Hypoxanthine,  238 

Hysteria,  Hoffmann's  anodyne  in,  271 
Hysteric  conditions,  camphor  in,  203 


Ichthyol,  47s 

as  intestinal  disinfectant,  476 
Idiosyncrasy,  dose  and,  50 
Ilex  cassine,  239 
Illuminating-gas,    poisoning   from,    532 

transfusion  of  blood  in,  212 
Immunity,  effect  of  anesthesia  on,  288 
Imperial  drink,  83 
Incompatibility,  58,  557 

chemic,  557 
Incompatibles.  alkaloids,  22 
Indian  tobacco,  405 
Indication,  definition,  62 
Inebriety,  327  Q 

Inertia,  uterine,  pituitary  extract  m,  198 
Infantile  wasting,  thyroid  gland  in,  522 
Infantilism,  pancreatic,  pancreatin  in. 

77 
Infections,  effect  of  anesthesia  on,  288 
Infectious  diseases,  digitalis  in,  185 
Infiltration  anesthesia,  Schleich's,  399 


Inflammation,  counterirritants  for,  73 
Influenza,  quinine  in,  450 
Infusion,  definition,  40 
intravenous,  55 
of  wild  cherry,  402 
Infusum,  definition,  40 
Ingluvin,  80 

in  nausea  and  vomiting  of  pregnancy, 
80 
Inhalation,      administration      through 

lungs  by,  55 
Inorganic  acids,  81 
action,  81 

poisoning  from,  treatment,  82 
therapeutics,  82 
toxicology,  82 
Insomnia,  hyoscine  in,  385 
Instruments,  surgical,  disinfectants  for, 

482  . 

Insufflation,    intratracheal,    anesthesia 

by,  292 
Intestinal  disinfectants,  483 
irritation,  bismuth  in,  495 
obstruction,  atropine  in,  382 
paralysis,  pituitary  extract  in,  198 
post-operative,    after    ether    anes- 
thesia, 2S1 
peristalsis,  morphine  in,  365 
worms,  anthelmintics  for,  107 
Intestines,    distention    of,    after    ether 
anesthesia,  281 
small,  as  factor  in  defecation,  in 
Intoxicants,  297 

Intracutaneous  administration,  54 
Intramuscular  administration,  53 

injection  of  epinephrine,  effects,  189 
Intratracheal     insufflation,     anesthesia 

by,  292  .  .         .        ,      ■       , 

Intravenous  administration  of  epineph- 
rine, 195 
dangers,  196 
effects,  189 
anesthesia,  292 
Bier's,  402 
paraldehyd,  346 
with  cocaine,  397  _ 
chloroform  anesthesia,  292 
ether  anesthesia,  292 
infusion,  55 

of  salt  solution,  212 
injection,  55 
local  anesthesia,  402 
medication,  55 
Inunction,  administration  by,  55 
Invertase,  27 
Iodide  fever,  51S 
Iodides,  515 

administration,  519 

and  alkaloids,  incompatibility,  22 

contraindications,  519 

in  actinomycosis,  518 


5§4 


INDEX 


Iodides  in  colloid  goiter,  519 

in  hyperthyroidism,  519 

in  syphilis,  518 

pharmacologic  action,  515-517 

preparations  and  doses,  515 

therapeutics,  518 

untoward  actions,  517 
Iodine,  465,  5 15 

absorption,  516 

and  alkaloids,  incompatibility,  22 

compound  solution,  515 

compounds,  antiseptic,  465 

content  of  thyroid  gland,  516,  519 

excretion,  516 

pharmacologic  action,  515-517 

phenol  compounds,  470 

therapeutics,  518 

tincture  of,  515 

untoward  actions,  517 

waters,  137 
Iodipin,  515 
Iodism,  chronic,  518 
Iodoform,  465,  515 

emulsion,  466 

poisoning,  466 
Iodol,  465 
Iodum,  515 
Ipecac,  523 

as  diaphoretic,  524 

as  expectorant,  524 

as  nauseant,  524 

dose,  523 

fluidextract,  dose,  523 

in  amebic  dysentery,  524 

preparations  and  doses,  523 

syrup,  dose,  523 

therapeutics,  524 

wine,  dose,  523 
Ipecacuanha,  523 
Iribh  whisky,  301 
Iron,  499 

absorption,  501 

and  ammonium  citrate,  500 
tartrate,  500 

and  potassium  tartrate,  500 

artificial  organic  compounds,  500 

as  antidote  in  arsenic  poisoning,  499, 

5°9 
as  antiseptic  and  disinfectant,  466 
as  astringent,  499 
as  disinfectant,  499 
as  hematinic,  499,  502 
carbonate,  500 
chloride,  500 
effects  on  blood,  501 
food,  50 t 

hypophosphite,  500 
in  anemia,  503 
in  chlorosis,  503 
in  functional  albuminuria,  503 
iodide,  500 


Iron,  masked,  501 

metallic,  500 

organic,  501 

phosphate,  500 

poisoning,  502 

pyrophosphate,  500 

reduced,  500 

salts  of  organic  acids,  500 

sulphate,  500 
dried,  500 

therapeutics,  502 

toxicology,  502 

wines,  500 
Irritant  drugs,  time  to  give.  55 
Irritants,  116 
Irritation,  57 
Isoamylamine,  525 
Iso-nitroso-antipyrine,  436 
Isophysostigmine,  411 
Isopilocarpine,  414 
Isotonic  solutions,  213 
Itching  of  vulva,  epinephrine  in,  195 


Jaborandi,  414 
Jaborine,  414 
Jalap,  dose,  127 

powder,  compound,  128 

resin  of,  dose,  127 
Jasmine,  yellow,  404 
Jaw,  fossy,  514 
Jervine,  222 
Jimson-weed,  370 
Juice,  definition,  41 
Juniper,  compound  spirit  of,  301 
Junket,  79 


Kamala  for  tape-worms,  no 

poisoning  from,' no 
Keratin,  37 
Kerosene  oil,  33 
Kidneys  after  ether  anesthesia,  281 

functions  of,  425,  426 

glomerulus  of,  functions,  426 

hog-back,  331 

tubules  of,  functions,  426,  427 
Kinotannic  acid,  30 
Knock-out  drops,  343 
Kola,  239 

habit,  252 
Kolliker's  schema  to  show  reflex  arc,  258 
Korsakoff's  psychosis,  327 


Labarraqve's  solution,  464 
Lactalbumin,  79 
Lactarius  torminosus,  418 
Lactase,  27 
Lactic  acid,  84 
Lactophenin,  436 


INDEX 


585 


Lactophosphate  of  lime,  syrup  of,  91 
Lactuca  virosa,  369 
Lactucarium,  369 

in  cough,  369 
Lady  Webster's  dinner  pills,  1 23 
Lager  beer,  299 
Lambert's   treatment  for  morphinism, 

364. 
Lanolin,  32 
Lard,  30 
Larkspur,  221 
Laryngitis,  ammonium  chloride  in,  210 

croupous,  calomel  in,  486 

tuberculous,  antipyrine  in,  443 
Larynx  disinfectants,  483 
Lassar's  paste,  455 
Latin  adjectives,  543 

adverbs,  544 

conjunctions,  545 

in  prescription  writing,  541 

nouns,  542 

prepositions,  544 

verbs,  544 
Laudanum,  352 
Laughing-gas,  295 

anesthesia,  295 
Laurocerasus,  402 

Lavender,  compound  tincture  of,  100 
Laxative,  flowers  of  sulphur,  117 

measures,  113 

phthalems,  124 

pills,  compound,  dose,  254 
Laxatives,  bile  salts,  117 

liquid  paraffin,  117 

manna,  116 

precipitated  sulphur,  117 

sodium  glycocholate,  117 
taurocholate,  117 

sublimed  sulphur,  117 

sulphur,  116 
lotum,  117 
praecipitatum,  117 
sublimatum,  117 

washed  sulphur,  117 

weak, 116 
Lazy  man  prescriptions,  549 
Lead,  489 

acetate,  489 

and  opium  wash,  353,  489 

colic,  490 

encephalopathy,  491 

oleate,  489 

palsy,  490 

plaster,  489 

poisoning,  490 
diagnosis,  491 
treatment,  492 
wrist-drop  in,  491 

preparations,  489 

subacetate,  489 

sulphate,  489 


Lead,  toxicology,  490 
Lead-water,  489 
Lecithin,  32,  515 
Leech,  232 

artificial,  233 
Lemonade,  83 
Lemon-juice,  41 
Leprosy,  carminatives  in,  98 
Leptandra,  127 

dose,  127 
Leukomains,  23 
Levant  wormseed,  108 
Levo-hyoscyamine,  371,  384 
Levulose,  28 

in  testing  functional  power  of  liver,  28 
Licorice,  21 

mixture,  compound,  523 

powder,  compound,  124 
Light  wine,  300 
Lily-of-the-valley,  150 
Lime,  chloride  of,  464 

chlorinated,  464 

syrup  of,  91 
Lime-water,  91 
Limonis  succus,  41 
Liniment,  definition,  41 
Linimentum,  definition,  41 

saponis  mollis,  32 
Linseed  oil,  30 
Lipoids,  32 
Liquefied  phenol,  471 
Liqueurs,  301 
Liquid  albolene,  33,  117 

extracts  of  malt,  299 

paraffin,  ^$,  117 

petrolatum,  ^$,  117 

prescriptions,  537 
measures,  538 

vaseline,  33,  117 

to  prevent  adhesions  in  abdominal 
surgery,  34 
Liquids,  administration,  539 

alcoholic,  41 

aqueous,  40 

miscellaneous,  41 

percentage,  38 
chemic,  38 
pharmaceutic,  38 
strength  of,  38 
Liquor  acidi  arsenosi,  504 

ammonii  acetatis,  210 

antisepticus,  470 

arseni  et  hydrargyri  iodidi,  504 

calcis,  91 

cresolis  compositus,  470 

definition,  40 

ferri  chloridi,  499 

ct  ammonii  acetatis,  210,  500 
subsulphatis,  499 
tersulphatis,  499 

formaldehydi,  476 


586 


INDEX 


Liquor  magnesii  citratis,  dose,  129 

plumbi  subacetatis,  489 
dilutus„  489 

potassii  arsenitis,  504 

sodii  boratis  compositus,  471 
Liquors,  distilled,  300 

from  malt  liquors,  301 

from  saccharine  fruit-juices,  301 

medicinal  dose,  303 

malt,  298 
Lithia  waters,  137 
Lithium,  86,  87 

carbonate,  87 

citrate,  94,  95 

in  gout,  87 

poisoning,  87 
Liver,  cirrhosis  of,  alcohol  and,  308,  309 

functional  power  of,  levulose  in  test^ 
ing,  28 

in  disposal  of  ammonia,  205,  206 

sluggish,  calomel  in,  121 
Lobelia,  405 

in  spasmodic  asthma,  405 
Local  action,  direct,  52 

remote,  52 
Locke's  solution  for  saline  infusion,  213 
Locomotor  ataxia,  strychnine  in,  265 
Loco-weed,  198 
Loop,  Moreau's,  saline  cathartics  and, 

132 
Losophan,  465 
Lotio  flava,  485 

nigra,  485 

plumbi  et  opii,  353,  489 
Lotion,  definition,  41 
Lugol's  solution,  515 
Lunar  caustic,  496 
Lungs,     administration     through,     by 

inhalation,  55 
Lupulin,  369 

fluidextract  of,  369 

oleoresin  of,  369 
Lysol,  470 


Madeira  wine,  300 

Mad-weed,  198 

Magendie's  solution,  353 

Magma  magnesiae,  90 

Magnan's  sign  in  acute  cocaine  poison- 
ing, 394 

Magnesia,  burnt,  90 
milk  of,  90 
dose,  129 

Magnesii  carbonas,  90 
oxidum,  90 

ponderosum,  90 

Magnesium,  90 
carbonate,  90 

dose,  129 
citrate,  dose,  129 


Magnesium  hydroxide,  90 
dose,  129 
oxide,  90 
dose,  129 
heavy, 90 
peroxide,  90 
poisoning,  90 
sulphate,  400 

as  anesthetic,  400,  401 
dose,  129 

effervescing,  dose,  129 
in  pain,  402 

in  physostigma  poisoning,  414 
in  shock,  401 
in  tetanus,  401 
poisoning  from,  133 
therapeutics,  401 
Malakin,  436,  457 
Malaria,  quinine  in,  450 
Malates,  85 

Male-fern  for  tape-worms,  no 
Malic  acid,  85 

Malnutrition,  cod-liver  oil  in,  67 
Malt,  extract  of,  67,  79 
liquid  extracts,  299 
liquors,  298 
Maltase,  27 
Manganese,  503 

dioxide,  503 
Manna,  28 

as  laxative,  116 
Mannite,  28 

Mannitol  hexanitrate,  effect,  228 
Maranta,  29 
Masked  iron,  501 
Massa,  definition,  42 
Massage  as  cathartic  measure,  114 
Mate,  239 
Materia  medica,  18 
Maximum  dose,  47 
Measures  and  weights,  43 
Mechanical  applications,  66 

measures,  18 
Mel,  definition,  41 
Melubrin,  457 
Menorrhagia,  ergot  in,  529 
Menstruum,  38 
Menthol,  99 

Menthol-camphor  in  pain,  203 
Mercurial  ointment  as  antiseptic,  485 

stomatitis,  487 
Mercurials,  cathartic,  120 
Mercuric    chloride    and    alkaloids,    in- 
compatibility, 22 
as  disinfectant,  484 
Mercury,  4S4 

as  antiseptic  and  disinfectant,  466 
as  disinfectant,  484 
elimination,  487 
in  syphilis,  485 
poisoning,  487 


INDEX 


587 


Mercury  subsulphate  in  croup,  486 

systemic  action,  487 

toxicology,  487 
Mesotan,  457 
Metallic  astringents,  105 

iron,  500 

salts,  caustic,  73 
Metals  and  their  compounds  as  anti- 
septics and  disinfectants,  466 

heavy,  483 
Methyl  alcohol,  335 

salicylate,  99 
Methyl-acetanilid,  436 
Methylene-blue  as  antiseptic,  476 
Methyl-ouabain,  150 
Methyl-oxymethyl    ester    of    salicylic 

acid,  457 
Methyloxypurins,  238 
Methyl  -  para  -  amido  -  metaoxyben- 

zoic  ester,  398 
Methyl-propyl-carbinol-urethane,  345 
Metric  prescriptions,  535 

system,  43 
Meyer-Overton  theory  of  narcosis,  275 
Milk,  clotting  of,  by  rennet,  calcium  in, 

93 

of  bismuth,  495 

of  magnesia,  90 

peptonizing,  pancreatin  for,  78 

sugar  of,  28 
Milk-punch,  302 
Mineral  oil,  Russian,  117 

oils,  33 

waters,  136 
Minimum  dose,  47 
Mistura,  definition,  40 

pectoralis,  151 

as  expectorant,  523 
Mitral  insufficiency,  digitalis  in,  183 

stenosis,  digitalis  in,  184 
Mixture,  definition,  40 
Moebius'  antithyroidin,  522 
Monkshood,  217 
Monobromated  camphor,  199 
Monobrom-valeryl-urea,  345 
Monoglycol  ester  of  salicylic  acid,  457 
Monohydrated  sodium  carbonate,  87 
Monsel's  solution,  499 
Moore  and  Roaf  theory  of  narcosis,  275 
Moreau's  loop,  saline  cathartics  and,  132 
Morning  tonic,  326 
Morphine,  352,  353 

absorption,  355 

acetate,  353 

and  atropine,  in  hypodermatic  use, 

365 
as  preliminary  to  general  anesthesia, 

365 
chlonde,  353 

contraindications  or  cautions,  365 
di-acetyl,  366 


Morphine,  dose,  353 

excretion,  360 

habit,  362 

in  cough,  357 

in  diabetes,  365 

in  intestinal  peristalsis,  365 

in  pain,  357,  365 

in  vomiting,  365 

pharmacologic  action,  353-361 

poisoning,  361,  362 

powder,  compound,  353 
•   sulphate,  353 

susceptibility,  361 

therapeutics,  364 

tolerance,  361 

toxicology,  361 

untoward  effects,  360 
Morphinism,  362 

Lambert's  treatment,  364 

pigment  atrophy  in,  364 

treatment,  363 
Mouth,  administration  by,  52 

disinfectants,  483 
Mucilage,  29 

definition,  40 
Mucilago,  40 

Murphy's  method  of  proctoclysis,  135 
Muscarine  poisoning,  417 
Muscular    inability    of    heart    without 
valvular  lesion,  digitalis  in,  182 

tone,  action  of  strychnine  on,  259 
Mushroom,  field,  419 

poisoning,  417 
treatment,  418 
Musk,  370 

dose,  370 
Mustard,  72 

foot-bath,  72 

oil  of,  volatile,  26 

paste,  72 
Mutual  helpers,  57 
Mydriatic,  definition,  378 
Myocarditis,  digitalis  in,  182 
Myricyl  palmitate,  33 
Myrosin,  25,  27 
Myrrh,  106 
Myxedema,  thyroid  gland  in,  521 


Name  of  patient  on  prescription,  536 
Naphthalin,  470 
Narcosis.  266 

alcohol,  stages,  313 

theories,  275 
Narcotics,  266 
Narcotine,  352 

Nasal  hemorrhage,  antipyrine  in,  443 
Nataloin,  124 
National  Formulary,  46 
Natural  emulsion,  41 


588 


INDEX 


Nauheim  bath  as  circulatory  stimulant, 

147 
Nausea  after  ether  anesthesia,  280 

bismuth  in,  495 

cerium  in,  495 

of  pregnancy,  treatment,  104 

of  seasickness,  treatment,  104,  105 
Neo-salvarsan,  505,  511 

in  syphilis,  511 
Nephritis,  acute,  diuresis  in,  433,  434 

chronic,  diuresis  in,  434 

diaphoresis  in,  423,  424 
Nerves,  blocking  of,  234 

cardio-inhibitory,  141 
Nervous  diseases,  atropine  in,  383 
calcium  in,  94 
strychnine  in,  265 

instability,  camphor  in,  203 

irritability,  bromides  in,  350 

stimulants,  peripheral,  411 

system,  central,  remedies  acting  on, 
238 
which  depress,  266 
peripheral,  drugs  affecting,  370 
Neuralgia,  quinine  in,  450 

trifacial,  aconite  in,  221 
alcohol  in,  333 

butyl  chloral  hydrate  in,  343 
gelsemium  in,  404 
vera  trine  in,  224 
Neuromuscular  junction,  receptive  sub- 
stance at,  143 
Neutral  principles,  24 
Nevi,  nitric  acid  for,  82 
Nicotiana  Rustica,  405 

tabacum,  405 
Nicotine,  405 

pharmacologic  action,  406,  407 

poisoning,  acute,  407 
Nightshade,  deadly,  370 
Night-sweats  of  tuberculosis,  sulphuric 

acid  in,  83 
Niter,  226 

as  preservative,  466 

sweet  spirit  of,  226 
Nitrates,  225 
Nitric  acid,  81 

action  of,  74 
Nitrites,  225 

administration,  231 

excretion,  229 

pharmacologic  action,  226-230 

poisoning  from,  230 

preparations  and  doses,  225 

therapeutics,  230 

toxicology,  230 
Nitrogenous  excretion,  relation  of  dia- 
phoresis to,  422 
Nitroglycerin,  225 

effect,  228 
Nitrohydrochloric  acid,  81 


Nitrous  ether,  spirit  of,  226 
oxide,  295 

anesthesia,  295 

preliminary   anesthetization   with, 
in  ether  anesthesia,  282 

Nodal  rhythm  of  heart  from  digitalis, 
161 

Node,  sinus,  action  of  digitalis  on  circu- 
lation through, 155 

Nomenclature  of  pharmaceutic  prepara- 
tions, 40 

Nose,  diseases  of,  cocaine  in,  395 
disinfectants,  483 

Nose-bleed,  counterriritants  for,  73 
epinephrine  in,  195 

Nouns,  Latin,  542 

Novaspirin,  456 

Novocaine,  398 

Nutrients,  66 

Nutritive  enema,  135 

Nux  vomica,  253 


Obesity,  thyroid  gland  in,  522 
Obstetrician's  hands,  disinfectants  for, 

482 
Occupation,  dose  and,  50 
Official  preparations,  45 
Oil,  almond,  30 
castor,  31,  118 

administration,  119 

therapeutics,  119 
cocoanut,  30' 
cod-liver,  30,  66 

emulsion  of,  67 

with  hypophosphites,  67 

in  malnutrition,  67 

preparations  and  doses,  67 
cottonseed,  30 
croton,  31,  127 

dose,  127 
linseed,  30 

of  bitter  almond,  25,  402 
of  cade,  35,  470 
of  cinnamon,  470 
of  cloves,  470 
of  mustard,  volatile,  26 
of  tar,  35 

of  turpentine  for  tape-worms,  no 
olive,  30,  118 
peanut,  30 
Russian  mineral,  117 
Oils,  animal,  30 
empyreumatic,  34 
essential,  34 
fixed,  30 

as  cathartics,  118 
mineral,  33 
vegetable,  30 
volatile,  34 

as  antiseptics,  470 


INDEX 


589 


Oils,  volatile,  occurrence  of,  34 
Ointment,  definition,  42 

of  ammoniated  mercury  as  antiseptic, 

485  .        . 

of  nitrate  of  mercury  as  antiseptic, 

485  ■        •       o 

of  yellow  oxide  as  antiseptic,  455 

Ointments,  33 

Oleate,  definition,  43 

Oleatum,  definition,  43 

Olein,  30 

Oleoresin,  definition,  41 

of  aspidium  for  hookworms,  109 

for  tape- worms,  no 

Oleoresina,  definition,  41 

Oleoresins,  36 

Oleum  cadinum,  35 

morrhuae,  30 

olivse,  118 

picis  liquidse,  35 

ricini,  31,  118 

theobromatis,  30 

tiglii,  31 

dose,  127 

Olive  oil,  30,  118 

Operative  measures,  18 

Ophthalmia,         gonorrheal,         Crede's 

method  of  prophylaxis  against,  496 

Opii  pulvis,  352 

Opium,  351 

absorption,  355 

alkaloids,  352 

camphorated  tincture,  dose,  352 

contraindications  or  cautions,  365 

deodorized,  352 

extract,  dose,  352 

granulated,  352 

in  diabetes,  365 

in  intestinal  peristalsis,  365 

in  pain,  357,  365 

in  vomiting,  365 

pharmacologic  action,  353-361 

pill,  dose,  352 

plaster,  352 

poisoning,  361 

chronic,  362 

pin-point  pupils  in,  359 

powdered,  352 

preparations  and  doses,  352 

therapeutics,  364 

tincture,  352 

to  induce  sleep,  365 

sweating,  365 

Optimum  rate  of  heart,  142 

Orexine  hydrochloride,  101 

tannate,  101 

Organic  acids,  83 

drugs,  constituents,  19 

active,  19,  20 

Orthoform,  398 

therapeutics,  398 


Osmosis,  213 

Osteomalacia,  phosphorus  in,  514 

thyroid  gland  in,  522 
Ouabain,  151 
dose,  151 

elimination  of,  173 
intramuscular  use,  186 
intravenous  use,  186 
Ovoferrin,  501 
Oxalic  acid,  85 

poisoning,  85 
Oxidases,  27 
Oxidizers,  463 
Oxygen,  534 
in  cyanosis,  534 
in  depressed  breathing,  534 
in  failure  of  circulation,  534 
in  pneumonia,  534 
inhalation    in   strychnine   poisoning, 

264 
pharmacologic  action,  534 
therapeutics,  534 
Oxymethyl  hydrastinine,  531 
Oxyntin,  83 
Oxypurins,  238 

Oxyuris  vermicularis,  remedies  for,  108 
Oxyxanthine,  238 


Pack,  cold-,  435 

hot-,  420 
Pain,  aconite  in,  221 

analgesic  antipyretics  in,  443 

atropine  in,  379 

bromides  in,  350 

cannabis  indica  in,  369 

chloral  hydrate  in,  342 

chloral-camphor  in,  203 

chloroform  in,  275 

Epsom  salt  in,  402 

humulus  in,  369 

in  back  after  ether  anesthesia,  281 

magnesium  sulphate  in,  402 

menthol-camphor  in,  203 

morphin  in,  357,  365 

salicylic  acid  in,  455 
Pains,  referred,  68 
Painter's  colic,  490 
Palmitin,  30 
Palsy,  lead,  490 

Pancreatic  infantilism,  pancreatin  in,  77 
Pancreatin,  76 

for  peptonizing  milk^  78 

in  chronic  pancreatitis,  77 
in  hyperthyroidism,  77 
in  pancreatic  infantilism,  77 
trypsin  of,  78 
Pancreatinum,  76 

Pancreatitis,  chronic,  pancreatin  in,  77 
Pantopon,  353 
dose,  3S3 


59° 


INDEX 


Papain,  80 

Papaver  somniferum,  351 

Paper,  definition,  42 

Para-amido-benzoic-acid-propyl     ester, 

399 
Para  -  amino  -  benzoyl  -  diethyl  -  amino  - 

ethanol  chloride,  398 
Para-diethoxyethenyl-  diphenyl  -  amidin 

chloride,  399 
Paraffin,  33 

liquid,  33,  117 
Paraffinum,  33 
Paraform,  476 
Paraguay  tea,  239 
Para-hydroxyphenyleth ylamine,  525 
Paraldehyd,  345 

habit,  346 

in  strychnine  poisoning,  264 

intravenous  anesthesia,  346 

poisoning  from,  346 
Paralysis,  57 

gastric   or   intestinal   post-operative, 
after  ether  anesthesia,  281 

intestinal,  pituitary  extract  in,  198 

respiratory,  collapse  and,  235 

strychnine  in,  265 

Sunday-morning,  326 
Pararegulin,  116 
Parathyroid    glands,    removal,    tetany 

after,  92 
Paregoric,  dose,  352 
Paroxysmal    tachycardia,    digitalis    in, 
179 
from  digitalis,  161 
Paste,  Lassar's,  455 

mustard,  72 
Pasteurization,  459,  462 
Peanut  oil,  30 
Pear  brandy, 301 

cider,  300 
Pelletierine  for  tape-worms,  no 
Pepo  for  tape-worms,  no 
Pepsin,  27,  76 
Pepsinum,  76 

Peptonizing  milk,  pancreatin  for,  78 
Percentage  liquids,  38 
chemic,  38 
pharmaceutic,  38 

strength  of  liquids,  38 
Perhydrol,  90 

Peripheral  nervous  stimulants,  411 
system,  drugs  affecting,  370 

resistance,  influences  affecting,  139 
Pernicious  anemia,  cholesterin  in,  32 
Peroxide  of  hydrogen,  463 
Peruvian  bark,  444 
Petrol,  33 
Petrolatum,  33 

album,  33 

liquid,  33,  117 

white,  33 


Petroleum  benzin,  33 

products,  33 
Pharmaceutic  chemistry,  18 

elixirs,  301 

measures,  18 

percentage  liquid,  38 

preparations,  37 
compound,  40 
definitions  of  kinds  in  common  use, 

40 
nomenclature,  40 
simple,  40 
Pharmacist,  18 
Pharmacodynamics,  18 
Pharmacognosist,  18 
Pharmacognosy,  18 
Pharmacologic  action,  62,  63,  64 
Pharmacologist,  18 
Pharmacology,  18 
Pharmacopoeia,  45 

definition,  45 

United  States,  45 
Pharmacy,  18 
Pharyngitis,  acute,  ammonium  chloride 

in,  210 
Phasic  arhythmia  from  digitalis,   157, 

166 
Phen-acetamide,  436 
Phenacetin,  436 

excretion,  442 

pharmacologic  action,  436-442 

poisoning  from,  442 

therapeutics,  443 

untoward  effects,  442 
Phenol,  471 

as  anesthetic,  399 

as  antiseptic,  475 

compounds,  467 

excretion,  473 

for  infected  cavities,  74 

glycerite,  471 

in  tetanus,  475 

liquefaction,  471 

liquefied,  471 

ointment,  471 

pharmacologic  action,  471-473 

poisoning,  473 
treatment,  474 

preparations,  471 

therapeutics,  475 

toxicology,  473 
Phenolphthalein  as  laxative,  124 
Phenolphthalein-agar,  1 25 
Phenolsulphonates,  non-toxic,  474 
Phenol-tetrachlorphthalein,  1 25 
Phenyl  salicylate,  456 
Phenyl-chinolin-carboxylic  acid,  458 
Phenyl-dimethyl-pyrazolon,  435 
Phlebotomy,  231 
Phlorhizin,  26 
Phloridzin,  26 


INDEX 


591 


Phlorizin,  26 
Phosphoric  acid,  81 

dilute,  therapeutics,  83 
Phosphorus,  513 

hypophosphites,  514 

in  osteomalacia,  514 

in  rickets,  5 14 

poisoning,  acute,  513 
chronic,  514 

therapeutics,  514 

toxicology,  513 
Phthaleins,  laxative,  124 
Physical  measures,  18 
Physiologic  limit  of  drug,  48 
Physiology  of  circulation,  139 
Physostigma,  411 

constituents,  411 

dose,  412 

excretion,  413 

extract,  dose,  412 

pharmacologic  action,  412,  413 

poisoning  from,  413 

preparations  and  doses,  412 

therapeutics,  414 

tincture,  dose,  412 

toxicology,  413 

venenosum,  411 
Physostigmine,  411 

as  cathartic,  116 

pharmacologic  action,  412,  413 

salicylate,  dose,  412 

sulphate,  dose,  412 
Pick-me-up,  326 
Picraconitine,  217 

Pigment  atrophy  in  morphinism,  364 
Pill,  definition,  42 
Pills,  Blaud's,  500 

enteric,  37,  540 
Pilocarpidine,  414 
Pilocarpine,  414 

as  diaphoretic,  417 

chloride,  dose,  414 

elimination,  417 

nitrate,  dose,  414 

pharmacologic  action,  415,  416 

poisoning  from,  417 

therapeutics,  417 

toxicology,  417 
Pilocarpus,'  414 

as  diaphoretic,  417 

constituents,  414 

dose,  414 

elimination,  417 

fluidextract,  dose,  414 

jaborandi,  414 

microphyllus,  414 

pharmacologic  action,  415,  416 

poisoning  from,  417 
treatment,  417 

therapeutics,  417 

toxicology,  417 


Pilula  antiperiodica,  445 
sine  aloe,  445 
definition,  42 
Piluke  cathartics  compositae,  128 

vegetabiles,  128 
Pink-root  for  round-worms,  109 
Pin-point  pupils  in  opium  poisoning,  359 
Pin-worms,  remedies  for,  108 
Piperazine,  458 
Pitch,  sassafras,  29 
Pituitary  extract,  196 
in  acromegaly,  196 

in  intestinal  paralysis,  198 
in  pulmonary  hemorrhage,  198 
in  shock,  198 
in  uterine  inertia,  198 
therapeutics,  198 
toxicity,  198 
Pituitrin  in  collapse,  236 

in  shock,  236 
Placebo,  61 

Plant  acids  and  their  salts,  20 
Plants,  essences  of,  34 
Plaster,  definition,  42 
lead,  489 
opium,  352 
Pleistopon,  353 
Plethora,  hydremic,  428 
Pleural  effusion,  calcium  chloride  in,  93 
Plumbum,  489 
Pluto  water,  138 

concentrated,  138 
Pneumatic  suit,  Crile's,  in  shock,  211, 

237 
Pneumonia,  camphor  in,  203 
digitalis  in,  185 
oxygen  in,  534 
quinine  in,  450 
Podophyllum,  127 
dose,  129 
resin  of,  dose,  127 
Poison,  cumulative,  47 

hemlock,  404 
Poison-cup,  418 
Poisoning  from  acetanilid,  442 
from  aconite,  220 
treatment,  221 
from  alcohol,  325 
after-effects,  326 
treatment,  326 
from  ammonia,  207,  208 
treatment,  208 
water,  207,  208 
from  analgesic  antip3Tetics,  442 
from  antimony,  513 
from  antipyrine,  442 
from  arsenic,  acute,  508 

iron  as  antidote,  499,  509 
treatment,  509 
chronic,  509 
treatment,  510 


592 


INDEX 


Poisoning  from  arsenic,  cumulative,  510 
from  aspidium,  no 
from  aspirin,  456 
from  atropine,  380 

treatment,  381 
from  barium,  199 
from  belladonna,  380 

treatment,  381 
from  bismuth,  494 
from  bitter  apple,  126 
from  boric  acid,  467 
from  bromides,  acute,  349 

chronic,  350 

treatment,  350 
from  caffeine,  247 

treatment,  247 
from  camphor,  202 
from  carbon  monoxide,  532 
acute,  533 
chronic,  533 

transfusion  of  bipod  in,  210 
treatment,  533 
from  calcium,  94 
from  carminatives,  97 
from  chloral  hydrate,  acute,  341 

chronic,  342 
from  chloroform,  delayed,  286 
from  coal-gas,  532 
from  cocaine,  acute,  394 
Magnan's  sign  in,  394 
treatment,  394 

chronic,  394 
treatment,  395 
from  colchium,  458 
from  colocynth,  126 
from  copper,  493 
from  cyanides,  403 
from  digitalis,  174 

cumulative,  176 

overwhelming  dose,  174 

single  large  dose  by  mouth,  175 

symptoms,  176,  177 

treatment.  178 
from  drastics,  1 26 

treatment.  126 
from  early  bird  mixture,  no 
from  epinephrine,  194 
from  ergot,  528 

chronic,  529 
from  ether,  269 
from  formaldehyd,  477 

treatment,  478 
from  granatum,  no 
from  inorganic  acids,  treatment,  82 
from  iodoform,  466 
from  iron,  502 
from  kamala,  no 
from  lead,  490 

diagnosis,  491 

treatment,  492 

wrist-drop  in,  491 


Poisoning  from  lithium,  87 
from  magnesium  sulphate,  133 
from  mercury,  487 

acute,  488 

treatment,  488 

chronic,  488 
treatment,  489 

salivation  in,  487 
from  morphine,  361,  362 

chronic,  362 

treatment,  362 
from  muscarine,  417 
from  mushroom,  417 

treatment,  418 
from  nicotine,  acute,  407 

treatment,  408 
from  nitrites,  230 
from  opium,  361 

chronic,  362 

pin-point  pupils  in,  359 
from  oxalic  acid,  85 
from  paraldehyd,  346 
from  phenacetin,  442 
from  phenol,  473 

treatment,  474 
from  phosphorus,  acute,  513 

chronic,  514 
from  physostigma,  413 
from  pilocarpus,  417 

treatment,  417 
from  potassium  chlorate,  105 

cyanide,  403 
treatment,  403 
from  quinine,  449 
from  ricin,  27 
from  salicylic  acid,  454 
from  saline  infusion,  216 
from  santonin,  108 

treatment,  109 
from  sodium  chloride,  88 
from  strychnine,  262 

treatment,  263 
from  sulfonal,  344 
from  thymol,  109 
from  thyroid  gland,  521 
from  tobacco,  407,  408 
from  trional,  344 
from  veratrum,  224 
from  veronal,  345 
Poisonous  fungi,  418 
Poisons,  protoplasm,  general,  56 
Poliomyelitis,  anterior,  epinephrine  in, 

Polyporus  albus,  386 

Pomegranate  root  bark  for  tape- worms, 

no 
Port  wine,  300 
Porter,  299 

Post  and  Nicoll's  bacteria  table,  460,461 
Postpartum    hemorrhage,    epinephrine 

in,  195 


INDEX 


593 


Postpartum   hemorrhage,     prevention, 

ergot  in,  529 
Potassa  sulphurata  in  acne,  117 
Potassium,  86,  87 
acetate,  94 
alum,  498 
bicarbonate,  86 
bisulphate,  26 
bitartrate,  94,  95 

dose,  129 
carbonate,  86 
chlorate,  105 

in  stomatitis,  105 
poisoning  from,  105 
citrate,  94 
dose,  129 

effervescing,  dose,  129 
cyanide,  402 

poisoning  from,  403 

treatment,  403 
therapeutics,  403 
hypochlorite,  solution  of,  464 
iodide,  231,  515 
nitrate,  226 

as  preservative,  466 
permanganate,  503 

as  antiseptic  and  deodorizer,  463 
sulphate,  dose,  129 
tartrate,  94 
dose,  129 
Poulsson's  experiment  with  strychnine, 

256 
Poultice,  definition,  42 
Poultices,  71 

clay,  71 
Powder,  definition,  42 
Powdered  opium,  352 
Precipitated  carbonate  of  zinc,  493 
chalk,  91 

sulphur  as  laxative,  117 
in  acne,  117 
Pregnancy,   nausea   and   vomiting   of, 
ingluvin  in,  80 
treatment,  104 
Prepared  chalk,  91 
Prepositions,  Latin,  544 
Prescription,  535 
abbreviations,  551 

special,  553 
aromatics,  539 
colors,  540 
compound,  545 
dating,  536 
directions  for  compounding,  537 

for  label,  537  _ 
figuring  quantities,  547 
flavors,  539 
form,  545 
Latin,  541 
lazy  man,  549 
liquid,  537 

38 


Prescription,  liquid,  measures,  538  _ 
name  and  quantity  of  each  ingredient, 

537. 
of  patient,  536 
of  apothecaries'  system,  535 
of  metric  system,  535 
shot-gun,  549 
signature,  537 
simple,  545 
superscription,  537 
sweetening  agents,  539 
vehicle,  539 
writing,  535 
good  usage,  549 
Preservatives,  459,  481 
food,  481 

for  anatomic  material,  481 
for  antitoxins,  481 
for  vaccines,  481 
pharmaceutic,  481 
Preventive  medicine,  17 
Proctoclysis,  Murphy's  method,  135 
Propaesin,  399 
Protargol,  497 
Protectives,  65 

as  antemetics,  104 
Protoplasm,  poisons,  general,  56 
Protoveratrine,  222,  223 

action,  223  _ 
Primus  virginiana,  402 
Pseudojervine,  222 
Pseudo-strophanthin,  150 
Psoriasis,  chrysarobin  in,  76 
Psychic  antiseptics,  471 
gastric  juice,  100,  306 
Psychosis,  Korsakoff's,  327 
Psychotherapeutic  measures,  18 
J,  Psychotrine,  523 

Psyllium  seeds  to  increase  bulk  ot  feces, 

116 
Ptomains,  23 

Ptomatropine,  23  # 

Pulmonary  arteries,  action  of  digitalis 
on  circulation  through,  170 
circulation,  145 

hemorrhage,  effect  of  epinephrine  on, 
191 
pituitary  extract  in,  198 
Pulse  in  anesthesia,  294 
Pulsus  alternans,  digitalis  in,  179 

from  digitalis,  167 
Pulvis  acetanilidi  compositus,  239,  436 
definition,  42 
jalapae  compositus,  128 
Pumpkin-seed  for  tape-worms,  110 
Pupils,  pin-point,  in  opium  poisoning, 

359 
Pure  alkaloids,  21 

solubility  of,  21 
Purgative,  113 

subcutaneous,  128 


594 


INDEX 


Purified  aloes,  123 

animal  charcoal,  102 
Purins,  238 
Pyramidon,  436 
Pyrogallol,  470 


Quassia-cups,  ioi 
Quebracho  as  expectorant,  522 
Quercitannin,  30 
Quinidine,  444 
Quinine,  21,  444 

absorption,  446 

administration,  451 

amaurosis,  447 

amblyopia,  447 

and  urea,  bimuriate  of,  444 

chloride  as  local  anesthetic,  449 

bisulphate,  21,  444 

bromide,  444 

chloride,  444 

chocolates,  451 

elimination,  447 

in  amebic  colitis,  449 

in  blackwater  fever,  450 

in  headache,  450 

in  influenza,  450 

in  malaria,  450 

in  neuralgia,  450 

in  pneumonia,  450 

in  skin  diseases,  450 

pharmacologic  action,  445-449 

poisoning  from,  449 

rash,  448 

salicylate.  444 

sulphate,  21,  444 

therapeutics,  449 

untoward  symptoms,  449 


Race,  dose  and,  50 
Rash,  ether,  270 

from  bromides,  349 

quinine,  448 
Receptive  substance  at  neuromuscular 

junction,  143 
Rectal  anesthesia,  291 

injections,  134 

irrigations  of  saline  solution,  133 

suppositories,  43,  136 

treatment,  134 
Rectum,  administration  by,  55 

disinfectants,  483 
Recuperative  power  of  heart,  action  of 

digitalis  on,  167 
Red  wine,  300 
Reddening,  68 
Reduced  iron,  500 
Referred  pains,  68 
Reflex  emetics,  103 
Reflexes,  256 


Reflexes,  convulsive,  259 
from  strychnine,  257 

coordinated,  257 

simple,  257 

varieties,  257 
Regulin,  115 
Remote  local  action,  52 
Rennet,  78 
Rennin,  78 
Repeated  doses,  47 
Resin  of  jalap,  dose,  127 

of  podophyllum,  dose,  127 

of  scammony,  dose,  127 
Resins,  36 

gum,  36,  41 
Resorcin,  470 
Resorcinol,  470 
Respiration,    artificial,     in    strychnine 

poisoning,  264 
Respiratory  disinfectants,  483 

paralysis,  collapse  and,  235 

troubles  after  ether  anesthesia,  281 
Retention  of  urine  from  digitalis,  171 
Rhamnus  frangula,  124 

purshiana,  124 
Rheum,  124 

Rheumatism,    chronic,    diaphoresis   in, 
424 

cimicifuga  in,  458 

formic  acid  in,  84 

salicylic  acid  in,  455 

sodium  bicarbonate  in,  90 
Rheumatoid  arthritis,  thyroid  gland  in, 

522 
Rhubarb,  124 

and  soda  mixture,  1 24 

pills,  compound,  123,  124 

powder,  compound,  124 
Rhythm,  coupled,  of  heart,  from  digi- 
talis, 166 

nodal,  of  heart,  from  digitalis,  161 

of  heart,  influences  affecting,  142 
normal,  156 

digitalis  in,  181 
reversed,  from  digitalis,  161 
Ricin,  27 

poisoning,  27 
Ricinus  communis,  27 
Rickets,  phosphorus  in,  514 

thyroid  gland  in,  522 
Ringer-Locke    solution    for    saline    in- 
fusion, 213 
Ringer's  solution  for  saline  infusion,  213 
Risiccol,  119 

Roaf  and  Moore  theory  of  narcosis,  275 
Rochelle  salts,  94 

dose,  129 
Round-worms,  remedies  for,  108 
Rubefacient,  68 
Rubijervine,  222 
Rum,  301 


INDEX 


595 


Russian  bath,  419 
mineral  oil,  117 


Sabadine,  222 
Sabadinine,  222 
Saccharin,  66 
Saccharum,  28 

lactis,  28 
Safrol,  99 
Sajodin,  515 
Sal  ammoniac,  209 

granulatus  effervescens,  definition,  42 
Salads  as  cathartic  measure,  115 
Salicin,  25,  457 
Salicyl  alcohol,  25 
Salicylic  acid,  451 

absorption,  453 

administration,  455 

as  surgical  antiseptic,  455 

dose,  452 

excretion,  454 

in  corns,  455 

in  diabetes,  455 

in  gout,  455 

in  pain,  455 

in  rheumatism,  455 

in  skin  diseases,  455 

in  sweating  of  feet  and  hands,  455 

in  warts,  455 

pharmacologic  action,  452-454 

poisoning  from,  454 

preparations  and  doses,  452 

therapeutics,  455 

toxicology,  454 
allies,  455 
jag,  454 
Salicylic-acetanilid,  457 
Salicyliden-para-phenetidin,  457 
Salicylism,  454 
Salicyl-paraphenetidin,  457 
Saligenin,  25 
Saline  cathartics,  128 

action,  129 

doses,  129 

in  constipation,  objections,  133 

Moreau's  loop  and,  132 

pharmacologic  action,  129-133 

preparations,  129 

therapeutics,  133 

time  to  give,  55 
infusion,  212 

by  enema,  216 

by  hypodermoclysis,  216 

colon  irrigations,  135 

continuous  drop  irrigation,  135 

Dawson's  solution,  213 

effects,  214,  215 
of  rate  of  flow,  215 
of  temperature  of  solution,  215 
on  respiration,  215 


Saline  infusion,  effects  when  volume  of 
blood    has    not  been  de- 
creased, 214 
is  below  normal,  215 
in  cholera,  216 
in  collapse,  216 
in  ether  collapse,  294 
in  hemorrhage,  216 
in  shock,  216 

in  strychnine  poisoning,  264 
in  toxemic  conditions,  216 
intravenous,  55 
Locke's  solution,  213 
normal,  213 
poisoning  by,  216 
rectal  irrigations,  135 
Ringer-Locke  solution,  213 
Ringer's  solution,  213 
therapeutics,  216 
toxicology,  216 
waters,  137,  138 
Saliphen,  457 
Salipyrine,  436 

Salivation  in  mercury  poisoning,  487 
Salol,  456 
Salophen,  436,  457 
Salt,  Epsom,  dose,  129 
Glauber's,  dose,  129 
Rochelle,  dose,  129 
Saltpeter,  226 

as  preservative,  481 
Salts,  alkaloidal,  21 

differences  in  physiologic  actions, 

24  _  _ 
solubility  of,  21 

bile,  117 

metallic,  caustic,  73 

of  tartar,  86 
Salvarsan,  505,  511 

after-effects,  512 

contraindications,  512 

in  syphilis,  511 

therapeutics,  511,  512 

untoward  effects,  512 
Salves,  t,3 

Santonica  for  round-worms,  108 
Santonin,  26,  108 

poisoning  from,  10S 
treatment,  109 
Santoninum,  108 
Sapo, 31, 118 

mollis,  32 
SarsapariUa,  compound  syrup  of,  124 
Sassafras  pith,  29 
Scabies,  sulphur  in,  117 
Scammony,  dose,  127 

resin  of,  dose,  127 
Scarlet  red,  74 

Schleich's  infiltration  anesthesia,  399 
Schnaaps,  301 
Scientific  therapeutics,  58 


596 


INDEX 


Scilla,  150 
Scoparius,  404 
Scopola,  370,  371 

carniolica,  370 

dose,  371 
Scopolamine,  384 

bromide,  372 
Scopolamine-morphine  anesthesia,  385 

as  preliminary  to  general  anesthesia, 

385 
Scotch  whisky,  301 
Seasickness,  strychnine  sulphate  in,  105 

treatment,  105 
Secretin,  80 
Secretion  threshold  in  diuresis,  431 

to  diminish  atropine,  381,  382 
Sedatives,  central,  as  antemetics,  104 

local,  as  antemetics,  104 
Selective  drugs,  56 
Semi-solids,  41 
Senega  as  expectorant,  522 
Senna, 124 
Serum,  Beebe's,  522 

sickness,  atropine  in,  383 
calcium  in,  94 
Sevum,  30 
Sex,  dose  and,  50 

Sexual  hyperesthesia,  bromides  in,  350 
Sheet,  drip,  435 

Sherrington's  theory  of  action  of  strych- 
nine on  muscles,  259 
Sherry  wine,  300 
Shock,  233 

alcohol  in,  334 

camphor  in,  203 

carbon  dioxide  in,  237 

cause,  Crile's  theory,  234 
Henderson's  theory,  234 

Crile's  pneumatic  suit  in,  211,  237 

epinephrine  in,  236 
•  Epsom  salt  in,  401 

glucose  in,  28 

magnesium  sulphate  in,  401 

pituitary  extract  in,  198 

pituitrin  in,  236 

saline  infusion  in,  216 

spinal  analgesia  in,  234 

symptoms,  235,  236 

transfusion  of  blood  in,  212,  237 

treatment,  235,  236 
Shot-gun  prescription,  549 
Sign,  Magnan's,  in  acute  cocaine  poison- 
ing, 394 
Signature  of  prescription,  537 
Silver,  496 

as  antiseptic,  497 
and  disinfectant,  466 

colloidal,  497 

nitrate,  496 

as  prophylactic  against  gonorrheal 
ophthalmia,  496 


Silver  nitrate  in  chronic  gastritis,  496 
in  hyperchlorhydria,  496 
therapeutics,  496 
protein,  497 
untoward  effects,  498 
vitellin,  497 
Simple  bitters,  101 
Sinalbin,  26 
Sinapine  sulphate,  26 
Sinapis,  72 
nigra,  72 
Sinigrin,  25 

Sinus  arhythmia,  digitalis  in,  179 
from  digitalis,  157 
node,  action  of  digitalis  on  circulation 
through,  155 
Sinuses,  chronic,  Beck's  treatment,  495 
Skin,  administration  by,  55 
diseases,  disinfectants  in,  483 
quinine  in.  450 
salicylic  acid  in,  455 
disinfectants,  482 
irritation,  production  of,  68 
Sleep,  335 

Verworn's  theory,  336 
Slippery  elm,  92 
Sluggish  liver,  calomel  in,  121 

ulcers,  burnt  alum  in,  498 
Smoking,  408 

effects  of,  410 
Snakeroot,  black,  458 
Snuff,  406 
Soamin,  504 
Soap,  31 

as  cathartic,  118 
Castile,  30,  31,  118 
green,  32 

tincture  of,  32 
hard,  31 
soft,  32 
Socaloin,  124 
Soda,  baking,  86 
Sodii  arsenas  exsiccatus,  504 
bicarbonas,  88 
nitris,  225 
Sodium,  86,  88 
acetate,  94 

aminophenyl  arsonate,  504 
arsanilate,  504 
arsenate,  504 

solution  of,  504 
benzoate,  469 
bicarbonate,  88 

administration,  in  ether  anesthesia, 

283 
effect  of,  on  alimentary  tract,  88 

on  mucous  membranes,  88 
in  acidosis,  89 
in  rheumatism,  90 
time  for  administering,  89 
bisulphite,  464 


INDEX 


597 


Sodium  borate  as  preservative,  466 
cacodylate,  504 
carbonate,  86 

monohydrated,  87 
chloride,  88 

as  preservative,  466 
poisoning,  88 
citrate,  94,  95 

dose,  129 
glycocholate,  117 
hydroxide,  30 

hypochlorite,  solution  of,  464 
hyposulphite,  464 
iodide,  515 
nitrite,  225 
dose,  225 
effect,  228 
perborate,  463 
phosphate,  dose,  129 

effervescing,  dose,  129 
sulphate,  dose,  129 
sulphite,  464 
tartrate,  94 
dose,  129 
taurocholate,  117 
thiosulphate,  464 
Soft  soap,  32 
Solid  albolene,  2,3 
Solids,  41 

administration,  540 
semi-,  41 
Solubility  of  alkaloidal  salts,  21 
of  alkaloids,  21 
of  atropine,  21 
sulphate,  22 
of  pure  alkaloids,  21 
Solution,  definition,  40 
of  aluminium  acetate,  498 
of  arsenous  acid,  504 
of  sodium  arsenate,  504 
Sore  tongue  after  ether  anesthesia,  281 
Spanish  fly,  72 
Sparkling  mineral  waters,  137 

wine,  300 
Sparteine  sulphate,  404 

in  spasmodic  asthma,  405 
Spasm,  Hoffmann's  anodyne  in,  271 

of  urethra,  cocaine  in,  396 
Spasmodic  asthma,  lobelia  in,  405 
sparteine  sulphate  in,  405 
stramonium  in,  384 
nervous  diseases,  atropine  in,  383 
Specific  treatment,  60 
Spermaceti,  33 
Spices,  99 

Spigelia  for  round-worms,  109 
Spinal  analgesia  in  shock,  234 

anesthesia   in    strychnine   poisoning, 
264 
with  cocaine,  389,  390,  396 
with  stovaine  and  strychnine,  390 


Spirit,  definition,  41 

of  bitter  almond,  403 

of  hartshorn,  204 

of  Mindererus,  210 

of  nitrous  ether,  226 
dose,  226 
Spirits,  300 
Spiritus  ammoniae  aromaticus,  204 

definition,  41 

frumenti,  301 

glycerylis  nitratis,  225 

vini  gallici,  301 
Spirosal,  457 
Splanchnic  organs,  action  of  pituitary 

extract  on,  197 
Spoonfuls,  538 
Spotted  boy,  498 
Squibb's  diarrhea  remedy,  136 

test  for  aconite,  21S 
Squill,  150 

compound  syrup  of,  151,  512 
as  expectorant,  523 

dose,  150 

syrup  of,  151 
Staphisagria,  221 
Starch,  arrowroot,  29 

corn-,  28 

water,  28 
Starches,  27 
Stavesacre,  221 
Stearin,  30 
Stearoptens,  35,  99 
Stenosis,  aortic,  digitalis  in,  184 

mitral,  digitalis  in,  1S4 
Sterilization,  459,  462 
Stimulants,  central  nervous,  238 

circulatory,  147 

peripheral  nervous,  411 
Stimulation,  56 
Stokes'  expectorant,  151,  522 
Stomach,  diseases  of,  cocaine  in,  396 

disinfectants,  483 

distention  of,  after  ether  anesthesia, 
281 

to  rectum,  passage  of  food  from,  time 
required,  112 

ulcer  of,  orthoform  in,  398 
scarlet  R  in,  75 
Stomatitis,  mercurial,  487 

potassium  chlorate  in,  105 
Stout,  299 
Stovaine,  397 

and    strychnine,     spinal    anesthesia 
with,  390 
Stramonium,  370,  371 

dose,  372 

in  spasmodic  asthma,  384 

ointment,  372 
Strong  wine,  300 
Stronger  ammonia  water,  204 
Strophanthin,  25,  150 


598 


INDEX 


Strophanthin,  dose,  150 

elimination  of,  173,  174 

intramuscular  use,  186 

intravenous  use,  186 

pseudo-,  150 
Strophanthus,  150 

absorption,    from    alimentary    tract, 

173 

constituents,  150 

dose,  150 

hispidus,  150 

Kombe,  150 

preparations  and  doses,  150 
reliability  of,  152 

tincture  of,  dose,  150 
Strychnine,  254 

absorption,  255 

administration,  266 

Bernard's  experiment,  256 

caffeine  and,   comparison  of  action, 
260 

contraindications,  266 

convulsive  reflexes  from,  257 

excretion,  262 

in  cough,  261 

in  diminished  vision,  265 

in  locomotor  ataxia,  265 

in  nervous  diseases,  265 

in  paralysis,  265 

nitrate,  254 
dose,  254 

pharmacologic  action,  254-262 

poisoning  from,  262 
treatment,  263 

poisonous  action,  260 

Poulsson's  experiment,  256 

preparations  and  doses,  254 

Sherrington's  theory,  259 

sulphate,  254 
dose,  254 
in  seasickness,  105 

testing  clinically,  261 

therapeutics,  264 

tolerance,  262 

toxicology,  262 
Strychnos  Nux-vomica,  253 
Stupe,  70 
Stupor,  266 

of  alcoholics,  325 
Stypticin,  531 
Styptics,  107 

Subcutaneous  administration,  52,  53 
superficial,  54 

injection  of  epinephrine,  effects,  188 

purgatives,  128 
Subinvolution  of  uterus,  ergot  in,  529 
Sublimed  sulphur  as  laxative,  117 
Succinyl  disalicylic  acid,  456 
Succus,  definition,  41 
Suet,  30 
Sugar  of  milk,  28 


Sugars,  27,  28 
Suggestive  measures,  18 
Sulfonal,  344 

poisoning,  344 
Sulphites,  464 

Sulphocarbolates,  non-toxic,  474 
Sulphonethylmethanum,  344 
Sulphonmethanum,  344 
Sulphur  as  laxative,  1 16 

dioxide,  464 

flowers  of,  as  laxative,  117 

in  scabies,  117 

lotum  as  laxative,  117 

praecipitatum  as  laxative,  117 

precipitated,  in  acne,  117 

sublimatum  as  laxative,  117 

sublimed,  as  laxative,  117 

washed,  as  laxative,  117 

waters,  137 
Sulphuric  acid,  81 
action  of,  74 
aromatic,  81 

in  night-sweats  of  tuberculosis,  83 
Sulphurous  acid,  464 
Sun  cholera  mixture,  136 
Sunday-morning  paralysis,  326 
Superheated  air,  425 
Superscription  of  prescription,  537 
Suppositorium,  definition,  43 
Suppository,  definition,  43 

glycerin,  31,  136 

rectal,  43,  136 

urethral,  43 

vaginal,  43 
Suppression  of  urine  from  digitalis,  171 
Supracapsulin,  186 
Suprarenal  gland,  dried,  dose,  187 
Suprarenalin,  186 
Suprarenine.  24 

Surgeon's  hands,  disinfectants  for,  482 
Surgical  instruments,  disinfectants  for, 
482 

supplies,  disinfectants  for,  482 
Susceptibility,  dose  and,  50 
Sweat,  character  of,  in  diaphoresis,  422 
Sweating,  419 

excessive,  agaricin  in,  386 

of  feet  and  hands,  salicylic  acid  in,  455 

profuse,  419 

rationale  of,  421 
Sweet  spirit  of  niter,  226 

wine,  300 
Sweetening  agents,  66 

for  prescription,  539 
Symptomatic  treatment,  60 
Synergists,  57 
Syphilis,  iodides  in,  518 

mercury  in,  485 

neo-salvarsan  in,  511 

salvarsan  in,  511 
Syrup,  definition,  40 


INDEX 


599 


Syrup  of  lactophosphate  of  lime,  91 

of  lime,  91 

of  phosphates  of  iron,  quinine  and 
strychnine,  dose,  254 

of  squill,  151 
compound,  151 

of  tar,  36,  470 

of  wild  cherry,  402 

of  yerba  santa,  102 
Syrupus  calcii  lactophosphatis,  91 

calcis,  91 

definition,  40 

picis  liquidae,  36,  470 
Systemic  action  of  drugs,  52 

arteries,  action  of  digitalis  on  circu- 
lation through, 168 


Tabacum,  405 
Tablet,  compressed,  541 
definition,  42 
hypodermic,  53,  541 
triturate,  definition,  42 
triturates,  541 
Tachycardia,  paroxysmal,  digitalis  in, 
179 
from  digitalis,  161 
Taenia   bothriocephalus,    remedies    for, 
no 
nana,  108 

remedies  for,  no 
saginata,  remedies  for,  no 
Taka-diastase,  80 
Tallow,  30 
Tannalbin,  107 
Tannate,  egg-albumin,  107 
Tannic  acid,  29,  106 

and  alkaloids,  incompatibility,  22 
astringents,  106 
of  coffee,  250 
of  tea,  250 
therapeutics,  107 
Tannigen,  107 
Tannin,  106 

formaldehyde-,  107 
hexamethylenamine-,  107 
Tanning,  106 
Tannins,  29 
Tannoform,  107 
Tannopin,  107 
Tape-worms,  dwarf,  remedies  for,  no 

remedies  for,  no 
Tar,  470 
oil  of,  35 
syrup  of,  36,  470 
Tartar,  cream  of,  94,  95 
dose,  129 
salts  of,  86 
Tartaric  acid,  83,  85 
Taste  of  alkaloids,  22 
Tea,  239,  249,  250 


Tea,  action,  251 
Appalache,  239 
black,  250 
green,  250 
habit,  251 
Paraguay,  249 
tannic  acid  of,  250 
tolerance,  252 
Temperature,  dose  and,  50 
Teniacides,  no 
Teniafuges,  no 
Test,  Falk  and  Tedesco's  salicylic,  453 

Squibb's,  for  aconite,  218 
Tetanus,  magnesium  sulphate  in,  401 

phenol  in,  475 
Tetany  after  removal   of   parathyroid 
glands,  92 
calcium  in,  92,  94 
Tetra-iodopyrrhol,  465 
Thebaine,  352 
Theobroma  cacao,  252 
Theobromine,  239,  249 
Theocin-acet-sodium,  249 
Theocine,  249 
Theophylline,  23,  249 
Therapeutic  dose,  47 
Therapeutics,  62 
definition  of,  17 
empiric,  58 
scientific,  58 
Thermal  mineral  waters,  137 
Thiersch's  solution,  467 
Thiol,  475 

Thiosinamine,  26,  75 
Thirst  after  ether  anesthesia,  281 
Thornapple,  370 

Thread-worms,  remedies  for,  108 
Throat,  diseases  of,  cocaine  in,  395 

disinfectants,  483 
Thymol  for  hookworms,  109 
iodide,  465,  470 
poisoning  from,  109 
Thyreoglobulin,  519 
Thyreoidectin,  522 
Thyroid  gland,  519 

after  thyroidectomy,  521 
in  colloid  goiter,  522 
in  cretinism,  521 

in  delayed  union  of  fractures,  522 
in  hypothyroidism,  521 
in  infantile  wasting,  522 
in  myxedema,  521 
in  obesity,  522 
in  osteomalacia,  522 
in  rheumatoid  arthritis,  522 
in  rickets,  522 
iodine  content,  516,  519 
pharmacologic  action,  520,  521 
poisoning  from,  521 
therapeutics,  521 
hyperactivity,  remedies  for,  522 


6oo 


INDEX 


Thyroidectomy,  thyroid  gland  after,  521 

Thyroiodin,  519 

Tinctura  antiperiodica,  444 

cinchonas  composita,  101 
dose,  444 

definition,  41 

gentianas  composita,  101 

lavandulae  composita,  100 
Tincture,  definition,  41 
Tobacco,  405 

amblyopia,  410 

effects  of  smoking,  410 

habit,  408 

heart,  411 

in  asthma,  406 

Indian,  405 

poisoning,  407,  408 

therapeutics,  406 

tolerance,  408 

toxicology,  407 
Toleration,  dose  and,  50 
Toluol-azotoluol-azobetanaphthol,  74 
Tongue,  sore,  after  ether  anesthesia,  281 
Tonic,  morning,  326 
Toothache,  chloral  hydrate  in,  342 

chloroform  in,  275 
Torpor,  266 
Toxalbumins,  26 
Toxemic  conditions,  saline  infusion  in, 

216 
Toxic  dose,  47 

myocarditis,  digital's  in,  182 
Toxicology,  definition,  62 
Toxins,  26 
Tragacanth,  29 
Transfusion  of  blood,  217 

conditions  indicating,  212 
in  shock  and  collapse,  237 
Treatment,  expectant,  60 

scope  of,  60 

specific,  60 

symptomatic,  60 
Trichloracetic  acid,  84 
Trichlorethyl-glycuronic  acid,  341 
Trifacial  neuralgia,  aconite  in,  221 
alcohol  in,  333 

butyl  chloral  hydrate  in,  343 
gelsemium  in,  404 
veratrine  in,  224 
Trimethyl-benzoxypiperidine,  397 
Trimethylxanthine,  239 
Trinitrin,  225 
Trional,  344 

poisoning,  344 
Trioxymethylanthraquinone,  122 
Trioxymethylene,  476 
Trioxypurin,  238 
Triturates,  tablet,  541 
Trituratio,  definition,  42 

elaterini,  42 
Trituration,  definition,  42 


Troche,  definition,  42 

Troches  of  licorice  and  opium,  dose,  352 

Trochiscus,  definition,  42 

Tropacocaine,  398 

Truxilline,  387 

Trypanosomiasis,  antimony  in,  513 

Trypsin,  27 

of  pancreatin,  78 
Tub-bath,  434 
Tuberculosis,  night-sweats  of,  sulphuric 

acid  in,  83 
Tuberculous  cavities,  Beck's  treatment, , 

495  .  . 

laryngitis,  antipyrine  in,  443 
Tubules  of  kidneys,  functions,  426,  427 
Tully  powder,  353 

dose,  353 
Turkish  bath,  419 

Turpentine,  oil  of,  for  tape-worms,  no 
Turpeth  mineral  in  croup,  486 
Tympanites,  carminatives  in,  97 

counterirritants  for,  73 
Typhoid  fever,  citric  acid  in,  83 
Tyramine,  525 

dose,  526 


Ulcer,  gastric,  scarlet  R  in,  75 
of  stomach,  orthoform  in,  398 
sluggish,  burnt  alum  in,  498 

Uncinaria  americana,  treatment  of,  109 

Unguentum,  definition,  42 

United  States  Pharmacopoeia,  45 

Urea,  diuretic  action,  429 

Uremia,  diaphoresis  in,  423 

Ureters,  action  of  caffeine  on,  247 

Urethane,  345 

Urethra,  disinfectants,  483 
spasm  of,  cocaine  in,  396 

Urethral  suppository,  43 

Urethritis,  copper  sulphate  in,  493 
zinc  sulphate  in,  493 

Uric-acid  diathesis,  atophan  in,  458 

Urinary  tract,   colon-bacillus  infection 
of,  Burow's  solution  in,  498 
disinfectants,  483 

Urine,  constituents,  427 
of  diuresis,  425.     See  also  Diuresis. 
retention  of,  from  digitalis,  171 
suppression  of,  from  digitalis,  171 

Urotropine,  24,  478 

U.  S.  P.,  45  . 

Uterine  inertia,  pituitary  extract  in,  198 

Uterus,  subinvolution  of,  ergot  in,  529 


Vaccines,  preservatives  for,  481 
Vagina,  disinfectants,  483 
Vaginal  suppository,  43 
Vaginismus,  cocaine  in,  396 
Vaginitis,  copper  sulphate  in,  493 


INDEX 


60 1 


Vaginitis,  zinc  sulphate  in,  493 
Vagus  center,  action  of  aconite  on,  219 
ganglia,  141 
system,  141 
depression,  142 
stimulation,  142 
Valerian,  369 

ammoniated  tincture  of,  100 

dose,  370 
fluidextract,  dose,  370 
preparations  and  doses,  370 
tincture,  dose,  370 
Vallet's  mass,  500 
Vapor  bath,  420 
Vaseline,  33 

in  dry  arthritis,  34 

liquid,  33,  117  .      LJ      .     , 

to  prevent  adhesions  m  abdominal 

surgery,  34 

white,  S3  ,    . 

Vasoconstriction  from  epinephrine,  169 

Vasoconstrictor  center,  action  of  aconite 

on,  219 
Vasoconstrictors,  143 
Vasodilators,  143 
Vasomotor  reversal,  527 
Vegetable  astringents,  106 
cathartic  pills,  1 28 
fats,  30 
oils,  30 
Vegetables  as  cathartic  measure,  115 
Vehicle  for  prescription,  539 
Veins,  administration  by,  55 
contraction  of,  144 
dilatation  of,  144 
Venesection,  231 

therapeutics,  232 
Venous  engorgement,  digitalis  in,  171 
Ventricle,    right,  of    heart,    action    of 

digitalis  on,  158 
Ventricular    fibrillation    from   digitalis, 

161 
Veratridine,  222 
Veratrine,  222,  223 
action,  223 
dose,  222 
ointment,  222 
oleate,  222 
Veratrum,  222 
action,  222 
album,  222 
constituents,  222 
dose,  222 

fluidextract,  dose,  222 
in  eclampsia,  224 
in  trifacial  neuralgia,  224 
poisoning  from,  224 
preparations  and  doses,  222 
therapeutics,  224 
tincture,  dose,  222 
toxicology,  224 


Veratrum  viride,  222 
Verbs,  Latin,  544 
Vermouth  wine,  302 
Veronal,  344 

poisoning,  345 

toxicology,  345 
Verworn's  theory  of  sleep,  336 
Vesicant,  68 
Vesicle-producing,  68 
Vinegar,  151 

definition,  41 
Vinum  album,  300 

definition,  41 

ferri,  500 

amarum,  500 

portense,  300 

rubrum,  300 

xericum,  300 
Vision,  diminished,  strychnine  in,  265 
Volatile  oil  of  mustard,  26 

oils,  34 

as  antiseptics,  470 
occurrence,  34 
Vomiting  after  anesthesia,  280 

and  nausea  of  pregnancy,  ingluvin  in, 
80 
treatment,  104 

bismuth  in,  495 

bromides  in,  350 

center,  action  of  aconite  on,  219 

cerium  in,  495 

chloroform  in,  275 

morphine  in,  365 

of  pregnancy,  treatment,  104 
Vulva,  itching  of,  cocaine  in,  396 
epinephrine  in,  195 

Warburg's  tincture,  444 

without  aloes,  445 
Warts,  nitric  acid  for,  82 

salicylic  acid  for,  455 
Wash,  black,  485 

lead  and  opium,  489 

yellow,  485 
Washed  sulphur  as  laxative,  117 
Water,  40 

as  diaphoretic,  419 

diuretic  action,  429 

Pluto,  138 

concentrated,  138 

starch,  28 
Water-retention,  digitalis  in,  172 
Waters,  acid,  137 

alkaline,  137,  138 
saline,  137,  138 

alum,  137 

arsenical,  137 

bromine,  137 

chalybeate,  137 

ferruginous,  137 


602 


INDEX 


Waters,  iodine,  137 
lithia,  137 
mineral,  136 

effervescent,  137 
non-effervescent,  137 
non-thermal,  137 
sparkling,  137 
thermal,  137 
saline,  137,  138 
sulphur,  137 
Wax,  bee's,  S3 
white,  S3 
yellow,  S3 
Waxes,  30,  32 
Weight,  bod)-,  dose  and,  48 
Weights  and  measures,  43 
apothecaries',  43 

exact  equivalents,  44 
metric,  43 
Wet  brain,  331 
Wet-cupping,  232 
Whey,  69 
Whisk}',  301 
corn,  300 
Irish,  301 
Scotch,  301 
White  arsenic,  503 
hellebore,  222 
petrolatum,  33 
precipitate    ointment    as    antiseptic, 

48S 

vaseline,  S3 

wax,  35 

wine,  300 
Whooping-cough,  antipyrine  in,  443 
Wild  cherry,  Buidextract  of,  402 
infusion  of,  402 
syrup  of,  402 
Wine,  definition,  41 

of  antimony.  5  1  2 

of  ipecac,  dose,  523 
Wines,  299 

dry,  300 

fortified,  300 

heavy, 300 

light,  300 

Madeira,  300 


Wines,  port,  300 

red,  300 

sherry,  300 

sparkling,  300 

strong,  300 

sweet,  300 

Vermouth,  302 

white,  300 
Wistar's  lozenges,  dose,  352 
Wood  alcohol,  335 
Wood-charcoal,  102 
Worms,  hook-,  treatment  of,  109 

intestinal,  anthelmintics  for,  107 

pin-,  remedies  for,  108 

round-,  remedies  for,  108 

tape-,  dwarf,  remedies  for,  no 
remedies  for,  no 

thread-,  remedies  for,  108 
Wormseed,  American,  109 

Levant,  108 
Wounds,  open,  disinfectants  in,  483 
Wristdrop  in  lead  poisoning,  491 


Xaxt:iixe,  238 


Yellow  jasmine,  404 

wash,  485 

wax,  35 
Yerba  santa,  iot,  400 

syrup  of,  102 
Yohimbine,  309 
Young's  rule  for  dosage,  49 


Zinc,  493 

as  antiseptic  and  disinfectant,  466 
carbonate,  493 
chloride,  493 
irritant  salts,  493 
ointment,  493 
oxide,  493 
soothing  salts,  493 
stearate,  493 
sulphate,  493 
Zincum,  493 


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Ophthalmology  for  Veterinarians.  By  Walter  N.  Sharp,  M.  D., 
Professor  of  Ophthalmology  in  the  Indiana  Veterinary  College.  i2mo 
of  210  pages,  illustrated.     Cloth,  $2.00  net. 

JUST  READY 

This  new  work  covers  a  much  neglected  but  important  field  of  veterinary 
practice.  Dr.  Sharp  has  presented  his  subject  in  a  concise,  crisp  way,  so  that 
you  can  pick  up  this  book  and  get  to  "the  point"  quickly.  He  first  gives  you  the 
anatomy  of  the  eye,  then  examination,  followed  by  the  various  diseases,  including 
injuries,  parasites,  errors  of  refraction,  and  medicines  used  in  ophthalmic  thera- 
peutics.    The  text  is  illustrated. 


SAUNDERS'     BOOKS    ON 


Barnhill  and  Wales' 
Modern   Otology 

A  Text=Book  of  Modern  Otology.  By  John  F.  Barnhill,  M.  D., 
Professor  of  Otology,  Laryngology,  and  Rhinology,  and  Earnest 
de  W.  Wales,  M.  D.,  Associate  Professor  of  Otology,  Laryngology, 
and  Rhinology,  Indiana  University  School  of  Medicine,  Indianapolis. 
Octavo  of  598  pages,  with  314  original  illustrations.  Cloth,  $5.50  net; 
Half  Morocco,  #7.00  net. 

THE  NEW  (2d)  EDITION 

The  authors,  in  writing  this  work,  kept  ever  in  mind  the  needs  of  the 
physician  engaged  in  general  practice.  It  represents  the  results  of  personal 
experience  as  practitioners  and  teachers,  influenced  by  the  instruction  given  by 
such  authorities  as  Sheppard,  Dundas  Grant,  Percy  Jakins,  Jansen,  and  Alt. 
Much  space  is  devoted  to  prophylaxis,  diagnosis,  and  treatment,  both  medical 
and  surgical.  There  is  a  special  chapter  on  the  bacteriology  of  ear  affections — 
a  feature  not  to  be  found  in  any  other  work  on  otology.  Great  pains  have  been 
taken  with  the  illustrations,  in  order  to  have  them  as  practical  and  as  helpful  as 
possible,  and  at  the  same  time  highly  artistic.  A  large  number  represent  the 
best  work  of  Mr.  H.  F.  Aitken. 


PERSONAL   AND    PRESS   OPINIONS 


Frank  Allport,  M.  D. 

Professor  of  Otology,  Northwestern  University,  Chicago. 

"  I  regard  it  as  one  of  the  best  books  in  the  English  language  on  this  subject.  The 
pictures  are  especially  good,  particularly  as  they  are  practically  all  original  and  not  the  old 
reproduced  pictures  so  frequently  seen." 

C.  C.  Stephenson,  M.  D. 

Professor  of  Ophthalmology  aud  Otology,  College  of  Physicians  and  Surgeons,  Little  Rock. 
Arkansas. 

"  To  my  mind  there  is  no  work  on  modern  otology  that  can  for  a  moment  compare  with 
'  Barnhill  and  Wales.'  " 

Journal  American  Medical  Association 

"  Its  teaching  is  sound  throughout  and  up  to  date.  The  strongest  chapters  are  those  on 
suppuration  of  the  middle  ear  and  the  mastoid  cells,  and  the  intracranial  complications  of  ear 
disease." 


DISEASES   OF   THE  EYE. 


DeSchweinitz's 
Diseases  of  the  Eye 

Just  Ready— The  New  (7th)  Edition 

Diseases  of  the  Eye :  A  Handbook  of  Ophthalmic  Practice. 
By  G.  E.  deSchweinitz,  M.D.,  Professor  of  Ophthalmology  in  the  Uni- 
versity oi  Pennsylvania,  Philadelphia,  etc.  Handsome  octavo  of  979 
pages,  360  text-illustrations,  and  7  chromo-lithographic  plates.  Cloth, 
$5.00  net;  Sheep  or  Half  Morocco,  $6.50  net. 

WITH  360  TEXT-ILLUSTRATIONS  AND  7  COLORED  PLATES 
THE  STANDARD  AUTHORITY 

Dr.  deSchweinitz' s  book  has  long  been  recognized  as  a  standard  authority 
upon  eye  diseases,  the  reputation  of  its  author  for  accuracy  of  statement  placing  it 
far  in  the  front  of  works  on  this  subject.  For  this  edition  Dr.  deSchweinitz  has 
subjected  his  book  to  a  most  thorough  revision.  Many  new  subjects  have  been 
added,  a  number  in  the  former  edition  have  been  rewritten,  and  throughout  the 
book  reference  has  been  made  to  vaccine  and  serum  therapy,  to  the  relation  of 
tuberculosis  to  ocular  disease,  and  to  the  value  of  tuberculin  as  a  diagnostic  and 
therapeutic  agent. 

The  text  is  fully  illustrated  with  black  and  white  cuts  and  colored  plates,  and 
in  every  way  the  book  maintains  its  reputation  as  an  authority  upon  the  eye. 


PERSONAL  AND   PRESS  OPINIONS 


Samuel  Theobald,  M.D., 

Clinical  Professor  of  Ophthalmology ,  Johns  Hopkins  University,  Baltimore. 
"  It  is  a  work  that  I  have  held  in  high  esteem,  and  is  one  of  the  two  or  three  books  upon 
the  eye  which  I  have  been  in  the  habit  of  recommending  to  my  students  in  the  Johns  Hopkins 
Medical  School." 

University  of  Pennsylvania  Medical  Bulletin 

"Upon  reading  through  the  contents  of  this  book  we  are  impressed  by  the  remarkable 
fulness  with  which  it  reflects  the  notable  contributions  recently  made  to  ophthalmic  literature. 
No  important  subject  within  its  province  has  been  neglected." 

Johns  Hopkins  Hospital  Bulletin 

"No  single  chapter  can  be  selected  as  the  best.  They  are  all  the  product  of  a  finished 
authorship  and  the  work  of  an  exceptional  ophthalmologist.  The  work  is  certainly  one  of  th« 
best  on  ophthalmology  extant,  and  probably  the  best  by  an  American  author." 


SAUNDERS'  BOOKS   ON 


GET  A  •  THE  NEW 

THE    BEST  I\  Hi  ©  T  1  C  Si  11  STANDARD 

Illustrated   Dictionary 

New  (6th)  Edition,  Entirely  Reset 


The  American  Illustrated  Medical  Dictionary.  A  new  and  com- 
plete dictionary  of  the  terms  used  in  Medicine,  Surgery,  Dentistry, 
Pharmacy,  Chemistry,  Veterinary  Science,  Nursing,  and  kindred 
branches;  with  over  ioo  new  and  elaborate  tables  and  many  illustra- 
tions. By  W.  A.  Newman  Dorland,  M.D.,  Editor  of  "  The  American 
Pocket  Medical  Dictionary."  Large  octavo,  with  986  pages,  bound  in 
full  flexible  leather.     Price,  $4.50  net;  with  thumb  index,  $5.00  net. 

KEY  TO  CAPITALIZATION  AND  PRONUNCIATION— ALL  THE  NEW  WORDS 

This  dictionary  is  the  "new  standard."  It  defines  hundreds  of  the  newest 
terms  not  defined  in  any  other  dictionary — bar  none.  These  terms  are  live, 
active  words,  taken  right  from  modern  medical  literature. 

Howard  A.  Kelly,  M.  D., 

Professor  of  Gynecologic  Surgery,  Johns  Hopkins  University ,  Baltimore 
"  Dr.  Dorland's  Dictionary  is  admirable.     It  is  so  well  gotten  up  and  of  such  convenient 
size.     No  errors  have  been  found  in  my  use  of  it." 

Theobald's  Prevalent  Eye  Diseases 


Prevalent  Diseases  of  the  Eye.  By  Samuel  Theobald,  M.  D., 
Clinical  Professor  of  Ophthalmology  and  Otology,  Johns  Hopkins 
University.  Octavo  of  5  50  pages,  with  219  text-cuts  and  several  colored 
plates.     Cloth,  $4.50  net ;  Half  Morocco,  #6.00  net. 

THE    PRACTITIONER'S    OPHTHALMOLOGY 

With  few  exceptions  all  the  works  on  diseases  of  the  eye,  although  written 
ostensibly  for  the  general  practitioner,  are  in  reality  adapted  only  to  the  specialist ; 
but  Dr.  Theobald  in  his  book  has  described  very  clearly  and  in  detail  those  condi- 
tions, the  diagnosis  and  treatment  of  which  come  within  the  province  of  the  general 
practitioner.  The  therapeutic  suggestions  are  concise,  unequivocal,  and  specific. 
It  is  the  one  work  on  the  Eye  written  particularly  for  the  general  practitioner. 

Charles  A.  Oliver.  M.D., 

Clinical  Professor  of  Ophthalmology,   Woman  s  Medical  College  of  Pennsylvania. 

"  I  feel  I  can  conscientiously  recommend  it,  not  only  to  the  general  physician  and  medical 
student,  for  whom  it  is  primarily  written,  but  also  to  the  experienced  ophthalmologist.  Most 
surely  Dr.  Theobald  1ms  accomplished  his  purpose." 


DISEASES   OF   THE  EYE. 


Haafo  and  DeSchweinitz's 
External  Diseases  qf  the  Eye 


Atlas  and  Epitome  of  External  Diseases  of  the  Eye.     By  Dr.  O. 

Haab,  of  Zurich.  Edited,  with  additions,  by  G.  E.  deSchweinitz, 
M.  D.,  Professor  of  Ophthalmology,  University  of  Pennsylvania.  With 
ioi  colored  illustrations  on  46  lithographic  plates  and  244  pages  of 
text.     Cloth,  $3.00  net.     In  Saunders1  Hand-Atlas  Series. 

THE   NEW   (3d)    EDITION 

Conditions  attending  diseases  of  the  external  eye,  which  are  often  so  complicated, 
have  probably  never  been  more  clearly  and  comprehensively  expounded  than  in 
the  forelying  work,  in  which  the  pictorial  most  happily  supplements  the  verbal 
description.     The  price  of  the  book  is  remarkably  low. 

The  Medical  Record,  New  York 

"  The  work  is  excellently  suited  to  the  student  of  ophthalmology  and  to  the  practising 
physician.     It  cannot  fail  to  attain  a  well-deserved  popularity." 

Haab  and  DeSchweinitz 's* 
Op  ht  halmoscopy 


Atlas  and  Epitome  of  Ophthalmoscopy  and  Ophthalmoscopic 
Diagnosis.  By  Dr.  O.  Haab,  of  Zurich.  Edited,  with  additions,  by 
G.  E.  deSchweinitz,  M.  D.,  Professor  of  Ophthalmology,  University 
of  Pennsylvania.  With  152  colored  lithographic  illustrations  and  92 
pages  of  text.     Cloth,  $3.00  net.     In  Saunders'  Hand- Atlas  Series. 

THE  NEW   (2d)    EDITION 

The  great  value  of  Prof.  Haab's  Atlas  of  Ophthalmoscopy  and  Ophthalmo- 
scopic Diagnosis  has  been  fully  established  and  entirely  justified  an  English 
translation.  Not  only  is  the  student  made  acquainted  with  carefully  prepared 
ophthalmoscopic  drawings  done  into  well-executed  lithographs  of  the  most  im- 
portant fundus  changes,  but,  in  many  instances,  plates  of  the  microscopic  lesions 
are  added.     The  whole  furnishes  a  manual  of  the  greatest  possible  service. 

The  Lancet,  London 

"We  recommend  it  as  a  work  that  should  be  in  the  ophthalmic  wards  or  in  the  library  of 
every  hospital  into  which  ophthalmic  cases  are  received." 


SAUNDERS'   BOOKS  ON 


Gradle's 
Nose,  Pharynx,  and  Ear 

Diseases  of  the  Nose,  Pharynx,  and  Ear.  By  Henry  Gradle, 
M.D.,  late  Professor  of  Ophthalmology  and  Otology,  Northwestern 
University  Medical  School,  Chicago.  Octavo  of  547  pages,  illustrated, 
including  two  full-page  plates  in  colors.     Cloth,  $3.50  net. 

INCLUDING  TOPOGRAPHIC  ANATOMY 

This  volume  presents  diseases  of  the  Nose,  Pharynx,  and  Ear  as  the  author 
has  seen  them  during  an  experience  of  nearly  twenty-five  years.  In  it  are 
answered  in  detail  those  questions  regarding  the  course  and  outcome  of  diseases 
which  cause  the  less  experienced  observer  the  most  anxiety  in  an  individual  case. 
Topographic  anatomy  has  been  accorded  liberal  space. 

Pennsylvania  Medical  Journal 

"This  is  the  most  practical  volume  on  the  nose,  pharynx,  and  ear  that  has  appeared 
recently.  ...  It  is  exactly  what  the  less  experienced  observer  needs,  as  it  avoids  the  confusion 
incident  to  a  categorical  statement  of  everybody's  opinion." 

Kyle's 
Diseases  of  Nose  and  Throat 


Diseases  of  the  Nose  and  Throat.  By  D.  Braden  Kyle,  M.  D., 
Professor  of  Laryngology  in  the  Jefferson  Medical  College,  Phila- 
delphia. Octavo,  797  pages;  with  219  illustrations,  26  in  colors. 
Cloth,  $4.00  net;  Half  Morocco,  #5.50  net. 

THE    NEW    (4th)    EDITION 

Four  large  editions  of  this  excellent  work  fully  testify  to  its  practical  value. 
In  this  edition  the  author  has  revised  the  text  thoroughly,  bringing  it  absolutely 
down  to  date.  With  the  practical  purpose  of  the  book  in  mind,  extended  con- 
sideration has  been  given  to  treatment,  each  disease  being  considered  in  full,  and 
definite  courses  being  laid  down  to  meet  special  conditions  and  symptoms. 
Pennsylvania  Medical  Journal 

"  Dr.  Kyle's  crisp,  terse  diction  has  enabled  the  inclusion  of  all  needful  nose  and  throat 
knowledge  in  this  book.  The  practical  man,  be  he  special  or  general,  will  not  search  in  rain 
for  anything  he  needs." 


URINE  AND   IMPOTENCE. 


Ogden  on  the  Urine 


Clinical  Examination  of  Urine  and  Urinary  Diagnosis.  A  Clinical 
Guide  for  the  Use  of  Practitioners  and  Students  of  Medicine  and  Sur- 
gery. By  J.  Bergen  Ogden,  M.  D.,  Medical  Chemist  to  the  Metro- 
politan Life  Insurance  Company,  New  York.  Octavo,  418  pages,  54 
text  illustrations,  and  a  number  of  colored  plates.     Cloth,  $3.00  net. 

THE  NEW  (3d)  EDITION 

In  this  edition  the  work  has  been  brought  absolutely  down  to  the  present  day. 
Urinary  examinations  for  purposes  of  life  insurance  have  been  incorporated,  because 
a  large  number  of  practitioners  are  often  called  upon  to  make  such  analyses. 
Special  attention  has  been  paid  to  diagnosis  by  the  character  of  the  urine,  the 
diagnosis  of  diseases  of  the  kidneys  and  urinary  passages  ;  an  enumeration  of  the 
prominent  clinical  symptoms  of  each  disease  ;  and  the  peculiarities  of  the  urine 
in  certain  general  diseases. 

The  Lancet,  London 

"  We  consider  this  manual  to  have  been  well  compiled  ;  and  the  author's  own  experience, 
so  clearly  stated,  renders  the  volume  a  useful  one  both  for  study  and  reference." 

Pilcher's 
Practical  Cystoscopy 

Practical  Cystoscopy.  By  Paul  M.  Pilcher,  M.  D.,  Consulting 
Surgeon  to  the  Eastern  Long  Island  Hospital.  Octavo  of  398  pages, 
with  233  illustrations,  29  in  colors.     Cloth,  $5.50  net. 

DIAGNOSIS  AND  TREATMENT 

Cystoscopy  is  to-day  the  most  practical  manner  of  diagnosing  and  treating 
diseases  of  the  bladder,  ureters,  kidneys,  and  prostate.  To  be  properly  equipped, 
therefore,  you  must  have  at  your  instant  command  the  information  this  book  gives 
you.  It  explains  away  all  difficulty,  telling  you  why  you  do  not  see  something 
when  something  is  there  to  see,  and  telling  you  how  to  see  it.  All  theory  has 
been  uncompromisingly  eliminated,  devoting  every  line  to  practical,  needed- 
every-day  facts,  telling  you  how  and  when  to  use  the  cystoscope  and  catheter — 
telling  you  in  a  way  to  make  you  know.      The  work  is  complete  in  every  detail. 

Bransford  Lewis,  M.  D.,  St.  Louis  University. 

"  I  am  very  much  pleased  with  Dr.  Pilcher's  '  Practical  Cystoscopy.'     I  think  it  is  the  best 

in  the  English  language  now." — April  27,  ign. 


io  SAUNDERS'   BOOKS    ON 

Goepp's 
Dental  State  Boards 

Dental  State  Board  Questions  and  Answers By  R.  Max  Goepp, 

M.  D.,  author  "  Medical  State  Board  Questions  and  Answers."     Octavo 
of  428  pages.     Cloth,  $2.75  net. 

COMPLETE  AND  ACCURATE 

This  new  work  is  along  the  same  practical  lines  as  Dr.  Goepp's  successful  work 
on  Medical  State  Boards.  The  questions  included  have  been  gathered  from  reliable 
sources,  and  embrace  all  those  likely  to  be  asked  in  any  State  Board  examination 
in  any  State.  They  have  been  arranged  and  classified  in  a  way  that  makes  for  a 
rapid  resume  of  every  branch  of  dental  practice,  and  the  answers  are  couched  in 
language  unusually  explicit — concise,  definite,  accurate. 

The  practicing  dentist,  also,  will  find  here  a  work  of  great  value — a  work 
covering  the  entire  range  of  dentistry  and  extremely  well  adapted  for  quick 
reference. 

Haab  arid  deSchweinitz's 
Operative  Ophthalmology 

Atlas  and   Epitome  of   Operative    Ophthalmology.       By  Dr.  O. 

Haab,  of  Zurich.  Edited,  with  additions,  by  G.  E.  de  Schweinitz, 
M.  D.,  Professor  of  Ophthalmology  in  the  University  of  Pennsylvania. 
With  30  colored  lithographic  plates,  1 54  text-cuts,  and  375  pages  of 
text.     In  Saunders1  Hand- Atlas  Series.     Cloth,  $3.50  net. 


Dr.  Haab's  Atlas  of  Operative  Ophthalmology  will  be  found  as  beautiful  and 
as  practical  as  his  two  former  atlases.  The  work  represents  the  author' s  thirty 
years'  experience  in  eye  work.  The  various  operative  interventions  are  described 
with  all  the  precision  and  clearness  that  such  an  experience  brings.  Recognizing 
the  fact  that  mere  verbal  descriptions  are  frequently  insufficient  to  give  a  clear 
idea  of  operative  procedures,  Dr.  Haab  has  taken  particular  care  to  illustrate 
plainly  the  different  parts  of  the  operations. 

Johns  Hopkins  Hospital  Bulletin 

"  The  descriptions  of  the  various  operations  are  so  clear  and  full  that  the  volume  can  well 
hold  place  with  more  pretentious  text-books." 


GENITO- URINARY  AND    NOSE,     THROAT,    ETC.  n 

Greene  and  Brooks' 
Genito-Urinary  Diseases 

Diseases  of    the   Genito=Urinary  Organs  and  the  Kidney.      By 

Robert  H.  Greene,  M.  D.,  Professor  of  Genito-Urinary  Surgery  at 
Fordham  University ;  and  Harlow  Brooks,  M.  D.,  Assistant  Pro- 
fessor of  Clinical  Medicine,  University  and  Bellevue  Hospital  Medical 
School.  Octavo  of  639  pages,  illustrated.  Cloth,  $5.00  net;  Half 
Morocco,  $6.50  net. 

THE  NEW   (3d)  EDITION 

This  new  work  presents  both  the  medical  and  surgical  sides.  Designed  as  a 
work  of  quick  reference,  it  has  been  written  in  a  clear,  condensed  style,  so  that 
the  information  can  be  readily  grasped  and  retained.  Kidney  diseases  are  very 
elaborately  detailed. 

New  York  Medical  Journal 

"  As  a  whole  the  book  is  one  of  the  most  satisfactory  and  useful  works  on  genito-urinary 
diseases  now  extant,  and  will  undoubtedly  be  popular  among  practitioners  and  students." 


Gleason  on  Nose,  Throat, 
and  Ear 

A   Manual   of   Diseases  of  the    Nose,  Throat,  and    Ear.     By  E. 

Baldwin  Gleason,  M.  D.,  LL.  D.,  Clinical  Professor  of  Otology, 
Medico-Chirurgical  College,  Philadelphia.  i2mo  of  556  pages,  pro- 
fusely illustrated.     Flexible  leather,  $2.50  net. 

THE  NEW  (2d)  EDITION 

Methods  of  treatment  have  been  simplified  as  much  as  possible,  so  that  ia 
most  instances  only  those  methods,  drugs,  and  operations  have  been  advised 
which  have  proved  beneficial.  A  valuable  feature  consists  of  the  collection  of 
formulas. 

American  Journal  of  the  Medical  Sciences 

"  For  the  practitioner  who  wishes  a  reliable  guide  in  laryngology  and  otology  there  are  few 
books  which  can  be  more  heartily  commended." 


American  Text-Book  of  Genito=Urinary  Diseases,  Syphilis,  and 
Diseases  of  the  Skin.  Edited  by  L.  Bolton  Bangs,  M.  D.,  and 
W.  A.  Hardaway,  M.  D.  Octavo,  1229  pages,  300  engravings,  20 
colored  plates.     Cloth,  $7.00  net. 


SAUNDERS'   BOOKS  ON 


Holland's  Medical 
Chemistry  and  Toxicology 

A  Text=Book  of  Medical  Chemistry  and  Toxicology.  By  James 
W.  Holland,  M.  D.,  Professor  of  Medical  Chemistry  and  Toxicology, 
and  Dean,  Jefferson  Medical  College,  Philadelphia.  Octavo  of  675 
pages,  fully  illustrated.     Cloth,  $3.00  net. 

THE  NEW  (3d)  EDITION 

Dr.  Holland's  work  is  an  entirely  new  one,  and  is  based  on  his  forty  years' 
practical  experience  in  teaching  chemistry  and  medicine.  It  has  been  subjected  to 
a  thorough  revision,  and  enlarged  to  the  extent  of  some  sixty  pages.  The  additions 
to  be  specially  noted  are  those  relating  to  the  electronic  theory,  chemical  equilib- 
rium, Kjeldahl's  method  for  determining  nitrogen,  chemistry  of  foods  and  their 
changes  in  the  body,  synthesis  of  proteins,  and  the  latest  improvements  in  urinary 
tests.      More  space  is  given  to  toxicology  than  in  any  other  text-book  on  chemistry. 

American  Medicine 

"  Its  statements  are  clear  and  terse ;  its  illustrations  well  chosen  ;  its  development  logical, 
systematic,  and  comparatively  easy  to  follow.  .  .  .  We  heartily  commend  the  work." 

Ivy's  Applied  Anatomy  and 

Oral  Surgery  for  Dental  Students 


Applied   Anatomy  and   Oral    Surgery  for  Dental  Students.    By 

Robert  H.  Ivy,  M.D.,  D.D.S.,  Assistant  Oral  Surgeon  to  the  Philadel- 
phia General  Hospital.      i2mo  of  280  pages,  illustrated.     Cloth,  $1.50 

net. 

FOR  DENTAL  STUDENTS 

This  work  is  just  what  dental  students  have  long  wanted— a  concise,  practical 
work  on  applied  anatomy  and  oral  surgery,  written  with  their  needs  solely  in 
mind.  No  one  could  be  better  fitted  for  this  task  than  Dr.  Ivy,  who  is  a  graduate 
in  both  dentistry  and  medicine.  Having  gone  through  the  dental  school,  he 
knows  precisely  the  dental  student's  needs  and  just  how  to  meet  them.  His 
medical  training  assures  you  that  his  anatomy  is  accurate  and  his  technic  modern. 
The  text  is  well  illustrated  with  pictures  that  you  will  find  extremely  helpful. 

H.  P.  Kuhn,  M.D.,  Western  Dental  College,  Kansas  City. 

"  I  am  delighted  with  this  compact  little  treatise.     It  seems  to  me  just  to  fill  the  bill." 


CHEMISTRY,   SKIN,  AND   VENEREAL   DISEASES.  13 

American  Pocket  Dictionary  New  (7th)  Edition 

The  American  Pocket  Medical  Dictionary.  Edited  by  W.  A. 
Newman  Dorland,  M.  D.,  Editor  "  American  Illustrated  Medical 
Dictionary."  Containing-  the  pronunciation  and  definition  of  the 
principal  words  used  in  medicine  and  kindred  sciences.  6lO  pages. 
Flexible  leather,  with  gold  edges,  $1.00  net;  with  thumb  index, 
#1.25  net. 

James  W.  Holland.  M.  D.. 

Professor  of  Medical  Chemistry  and  Toxicology,  and  Dean,  Jefferson  Medical  College, 

Philadelphia, 
"  I  am  struck  at  once  with  admiration  at  the  compact  size  and  attractive  exterior.     ] 
can  recommend  it  to  our  students  without  reserve." 

Stelwagon's  Essentials  of  Skin  7th  Edition 

Essentials  of  Diseases  of  the  Skin.  By  Henry  W.  Stel- 
WAGON,  M.  D.,  Ph.D.,  Professor  of  Dermatology  in  the  Jeffer- 
son Medical  College,  Philadelphia.  Post-octavo  of  29 1  pages, 
with  72  text-illustrations  and  8  plates.  Cloth,  $1.00  net.  In 
Saunders'  Question- Compend  Series. 
The  Medical  News 

"  In  line  with  our  present  knowledge  of  diseases  of  the  skin.  .  .  .  Continues  to  main- 
tain the  high  standard  of  excellence  for  which  these  question  compends  have  been  noted." 

Wolffs  Medical  Chemistry  New  (7th)  Edition 

Essentials  of  Medical  Chemistry,  Organic  and  Inorganic. 
Containing  also  Questions  on  Medical  Physics,  Chemical  Physiol- 
ogy, Analytical  Processes,  Urinalysis,  and  Toxicology.  By  Law- 
rence Wolff,  M.  D.,  Late  Demonstrator  of  Chemistry,  Jefferson 
Medical  College.  Revised  by  A.  Ferree  Witmer,  Ph.  G.,  M.  D., 
Formerly  Assistant  Demonstrator  of  Physiology,  University  of 
Pennsylvania.  Post-octavo  of  222  pages.  Cloth,  $1.00  net.  In 
Saunders1  Question-Compend  Series. 

Martin's  Minor  Surgery,  Bandaging,  and  the  Venereal 

Diseases  Second  Edition,  Revised 

Essentials  of  Minor  Surgery,  Bandaging,  and  Venereal 
Diseases.  By  Edward  Martin,  A.  M.,  M.  D.,  Professor  of  Clin- 
ical Surgery,  University  of  Pennsylvania,  etc.  Post-octavo,  166 
pages,  with  78  illustrations.  Cloth,  #1.00  net.  In  Saunders' 
Question-  Compend  Scries. 

Vecki's  Sexual  Impotence  New  (4*)  Edition 

Sexual  Impotence.  By  Victor  G.  Vecki,  M.  D.,  Consulting 
Genito-Urinary  Surgeon  to  Mt.  Zion  Hospital,  San  Francisco. 
l2mo  of  400  pages.     Cloth,  $2.25  net. 

Johns  Hopkins  Hospital  Bulletin 

"A  scientific  treatise  upon  an  important  and  much  neglected  subject.  .  .  .  The 
treatment  of  impotence  in  general  and  of  sexual  neurasthenia  is  discriminating  and 
judicious." 


14  SAUNDERS'    BOOKS   ON 

Wells'  Chemical  Pathology 

Chemical  Pathology.  Being  a  discussion  of  General  Path- 
ology from  the  Standpoint  of  the  Chemical  Processes  Involved. 
By  H.  Gideon  Wells,  Ph.  D.,  M.  D.,  Assistant  Professor  of 
Pathology  in  the  University  of  Chicago.  Octavo  of  549  pages. 
Cloth,  $3.25  net;  Half  Morocco,  $4.75  net. 

Win.   H.  Welch,   M.  D.,  Professor  of  Pathology,  Johns  Hopkins  University. 

"  The  work  fills  a  real  need  in  the  English  literature  of  a  very  important  subject,  and 
I  shall  be  glad  to  recommend  it  to  my  students." 


The  New   (2d  J  Edition 


Saxe's  Urinalysis 

Examination  of  the  Urine.  By  G.  A.  De  Santos  Saxe,  M.  D., 
formerly  Instructor  in  Genito-Urinary  Surgery,  New  York  Post- 
graduate Medical  School  and  Hospital.  i2mo  of  448  pages,  fully 
illustrated.     Cloth,  $1.75  net. 

Francis  Carter  Wood,  M.  D.,    Adjunct  Professor  of  Clinical  Pathology,   Columbia   Uni- 
versity. 

"  It  seems  to  me  to  be  one  of  the  best  of  the  smaller  works  on  this  subject ;  it  is, 
indeed,  better  than  a  good  many  of  the  larger  ones." 

deSchweinitz  and  Randall   on  the  Eye,  Ear, 
Nose,  and  Throat 

American  Text-Book  of  Diseases  of  the  Eye,  Ear,  Nose,  and 
Throat.  Edited  by  G.  E.  de  Schweinttz,  M.D.,  and  B.  Alex- 
ander Randall,  M.D.  Imperial  octavo,  1251  pages,  with  766 
illustrations,  59  of  them  in  colors.  Cloth,  $7.00  net;  Half  Mo- 
rocco, $8.50  net. 

Grunwald  and  Grayson  on  the  Larynx 

Atlas  and  Epitome  of  Diseases    of  the  Larynx.     By  Dr.  L. 

Grunwald,  of  Munich.  Edited,  with  additions,  by  Charles  P. 
Grayson,  M.D.,  University  of  Pennsylvania.  With  107  colored 
figures  on  44  plates,  25  text-cuts,  and  103  pages  of  text.  Cloth, 
$2.50  net.     hi  Saunders'  Hand-Atlas  Series. 

Mracek  and  Stelwagon's  Atlas  of  Skin         {*££! 

Atlas  and  Epitome  of  Diseases  of  the  Skin.  By  Prof.  Dr. 
Franz  Mracek,  of  Vienna.  Edited,  with  additions,  by  Henry 
W.  Stelwagon,  M.D.,  Jefferson  Medical  College.  With  77  col- 
ored plates,  50  half-tone  illustrations,  and  280  pages  of  text.  In 
Saunders'  Hand-At/as  Series.     Cloth,  $4.00  net. 


EYE,    EAR,    NOSE,    AND    THROAT.  15 

deSchweinitz   and    Holloway  on  Pulsating    Exoph- 
thalmos 

Pulsating  Exophthalmos.  An  analysis  of  sixty-nine  cases  not  pre- 
viously analyzed.  By  George  E.  deSchweinitz,  M.  D.,  and  Thomas 
B.  Holloway,  M.  D.     Octavo  of  125  pages.     Cloth,  $2.00  net. 

This  monograph  consists  of  an  analysis  of  sixty-nine  cases  of  this  affection 
not  previously  analyzed.  The  therapeutic  measures,  surgical  and  otherwise, 
which  have  been  employed  are  compared,  and  an  endeavor  has  been  made 
to  determine  from  these  analyses  which  procedures  seem  likely  to  prove  of 
the  greatest  value.  It  is  the  most  valuable  contribution  to  ophthalmic  liter- 
ature within  recent  years. 

British  Medical  Journal 

"  The  book  deals  very  thoroughly  with  the  whole  subject  and  in  it  the  most  complete  account  of 
the  disease  will  be  found." 

Jackson     On    the     Eye  The  New  (2d)  Edition 

A  Manual  of  the  Diagnosis  and  Treatment  of  Diseases  of  the 
Eye.  By  Edward  Jackson,  A.  M.,  M.  D.,  Professor  of  Ophthalmology, 
University  of  Colorado.  i2mo  volume  of  615  pages,  with  184  beautiful 
illustrations.     Cloth,  $2.50  net. 

The  Medical  Record,  New  York 

"  It  is  truly  an  admirable  work.  .  .  .  Written  in  a  clear,  concise  manner,  it  bears  evidence  of  th€ 
author's  comprehensive  grasp  of  the  subject.  The  term  '  multum  in  parvo'  is  an  appropriate  one  to 
apply  to  this  work." 

Grant  on  Face,   Mouth,  and  Jaws 

A  Text-Book  of  the  Surgical  Principles  and  Surgical  Diseases 
of  the  Face,  Mouth,  and  Jaws.  For  Dental  Students.  By  H.  Horace 
Grant,  A.  M.,  M.  D.,  Professor  of  Surgery  and  of  Clinical  Surgery, 
Hospital  College  of  Medicine,  Louisville.  Octavo  of  231  pages,  with 
68  illustrations.     Cloth,  $2.50  net. 

Preiswerk  and  Warren's  Dentistry 

Atlas  and  Epitome  of  Dentistry.  By  Prof.  G.  Preiswerk,  of 
Basil.  Edited,  with  additions,  by  George  W.  Warren,  D.D.S.,  Pro- 
fessor of  Operative  Dentistry,  Pennsylvania  College  of  Dental  Surgery, 
Philadelphia.  With  44  lithographic  plates,  152  text-cuts,  and  343  pages 
of  text.      Cloth,  $3.50  net.     In  Saunders'  Atlas  Series. 

Friedrich  and   Curtis  on  Nose,   Larynx,  and   Ear 

RHINOLOGY,   L-ARYNGOLOGy,  AND    OTOLOGY,    AND   THEIR    SIGNIFICANCE 

in  General  Medicine.  By  Dr.  E.  P.  Friedrich,  of  Leipzig.  Edited 
by  H.  Holbrook  Curtis,  M.  D.,  Consulting  Surgeon  to  the  New  York 
Nose  and  Throat  Hospital.  Octavo  volume  of  350  pages.  Cloth, 
$2.50  net. 


1 6  SAUNDERS'  BOOKS  ON 

Wolfs  Examination  of  Urine 

A  Laboratory  Handbook  of  Physiologic  Chemistry  and 
Urine-examination.  By  Charles  G.  L.  Wolf,  M.  D.,  Instructor  in 
Physiologic  Chemistry,  Cornell  University  Medical  College,  New 
York.  i2mo  volume  of  204  pages,  fully  illustrated.  Cloth,  $1.25  net. 
British  Medical  Journal 

"  The  methods  of  examining  the  urine  are  very  fully  described,  and  there  are  at  the 
end  of  the  book  some   extensive   tables  drawn  up  to  assist  in  urinary  diagnosis." 

Jackson's  Essentials  of  Eye  Third  Revised  Edition 

Essentials  of  Refraction  and  of  Diseases  of  the  Eye.  By 
Edward  Jackson,  A.  M.,  M.  D.,  Emeritus  Professor  of  Diseases  of 
the  Eye,  Philadelphia  Polyclinic.  Post-octavo  of  261  pages,  82  illus- 
trations. Cloth,  $1.00  net.  In  Saunders'  Question- Compend  Series. 
Johns  Hopkins  Hospital  Bulletin 

"  The  entire  ground  is  covered,  and  the  points  that  most  need  careful  elucidation 
are  made  clear  and  easy." 

Gleason's  Nose  and  Throat  Fourth  Edition,  Revised 

Essentials  of  Diseases  of  the  Nose  and  Throat.  By  E.  B. 
Gleason,  S.  B.,  M.  D.,  Clinical  Professor  of  Otology,  Medico- 
Chirurgical  College,  Philadelphia,  etc.  Post-octavo,  241  pages,  1 12 
illustrations.     Cloth,  $1.00  net.     In  Saunders'  Question  Compends, 

The  Lancet,  London 

"  The  careful  description  which  is  given  of  the  various  procedures  would  be  sufficient 
to  enable  most  people  of  average  intelligence  and  of  slight  anatomical  knowledge  to 
make  a  very  good  attempt  at  laryngoscopy." 

Gleason's  Diseases  of  the  Ear  Third  Edition,  Revised 

Essentials  of  Diseases  of  the  Ear.     By  E.  B.  Gleason,  S.  B., 
M.  D.,  Clinical  Professor  of  Otology,  Medico-Chirurgical  College, 
Phila.,  etc.     Post-octavo  volume  of  214  pages,  with   114  illustra- 
tions.    Cloth,  $  1. 00  net.     In  Saunders'  Question- Compend  Series. 
Bristol  Medico-Chirurgical  Journal 

"  We  know  of  no  other  small  work  on  ear  diseases  to  compare  with  this,  either  in 
freshness  of  style  or  completeness  of  information." 

Wilcox  on  Genito- Urinary  and  Venereal  Diseases 

The  New   (2d)   Edition 

Essentials  of  Genito-Urinary  and  Venereal  Diseases.  By 
Starling  S.  Wilcox,  M.  D.,  Lecturer  on  Genito-Urinary  Diseases 
and  Syphilology,  Starling-Ohio  Medical  College,  Columbus.  1 2mo 
of  321  pages,  illustrated.     Cloth,  $1. 00  net.     Saunders'  Compe?ids. 

Stevenson's  Photoscopy 

Photoscopy  (Skiascopy  or  Retinoscopy).  By  Mark  D.  Stev- 
enson, M.  D.,  Ophthalmic  Surgeon  to  the  Akron  City  Hospital. 
i2mo'of  126  pages,  illustrated.  Cloth,  $1.25  net. 

Edward  Jackson,  M.  D.,  University  of  Colorado. 

"  It  is  well  written  and  will  prove  a  valuable  help.  Your  treatment  of  the  emergent 
pencil  of  rays,  and  the  part  falling  on  the  examiner's  eye,  is  decidedly  better  than  any 
previous  account." 


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